PPM ACCESS
Access to the PPM Journal and newsletters is FREE for clinicians.
19 Articles in Volume 20, Issue #2
20/20 with Peter Staats, MD: The Future of Pain Medicine
Ask the APP: How useful and practical are pain assessment tools?
Ask the PharmD: What are the recommendations for preventing and treating pediatric migraine?
Axial Spondyloarthritis: Updated Medication and Imaging Recommendations
CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using A Checklist
Chronic Low Back Pain: Can We Find a Treatment Consensus?
Correspondence: Are ESIs Still Worth It? Benzocaine for Orofacial Pain.
Could Pulsed RF Provide Lasting Chronic Headache Relief in Refractory Patients?
Diagnosis Is Everything: Low Back Pain As a Symptom of an Underlying Condition or Conditions
Editorial: From Just Say No, to Say Now and Say Know
Erenumab and Onabotulinumtoxin A Show Additive Effect in Refractory Chronic Migraine
Experts Roundtable: Finding a Bottom Line in Back Pain Care
Inside the Potential of RNAi to Target the Etiology of hATTR Neuropathy
Muscle Dysfunction in Head and Neck: Pain Causes, Osteopathic Options
New Migraine Medications: Oral Gepants, Ditan Tablet, and More
Root Cause of Sacroiliac Joint Dysfunction: Four-Step Exercise Protocol
The Emotional Impact of Chronic Low Back Pain
The Rise in Tianeptine Abuse: Our Next Kratom Problem?
The Sensory Component of Pain: Modifying Its Emotional and Cognitive Meaning

CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using A Checklist

The authors propose that use of a supplemental clinical checklist may greatly increase the chance of identifying side effects during research trials and potentially in routine practice.
Pages 48-52

The calcitonin gene-related peptide (CGRP) monoclonal antibodies have proven to be reasonably effective in adult migraine prevention since their entry to market beginning in the spring of 2018. However, as previously reported by the authors,1,2 there are considerable adverse effects attributable to this new class of drugs that must be acknowledged and monitored. It is possible that clinical trials for these new products missed potential adverse effects by not using a checklist. Here, the authors explore how a checklist may be useful when prescribing CGRP inhibitors for migraine prevention in order to supplement and compare with usual assessment methods.

A supplemental checklist may help to examine adverse effects to develop a more realistic picture of the true adverse effects occurring in a given patient while on CGRP or another specific therapy. (Image: iStock)

Herein, the term “adverse events” is used to describe an abnormal occurrence reported by the patient while on the monoclonal antibody (mAb) but unable to be attributed to the mAb with certainty. The term “adverse effects” is used only when it is reasonable to conclude that the mAb was a primary factor in causing the problem. To be considered an adverse effect, the mAb should have been “more likely than not” to be the reason behind the adverse effect.

The purpose for examining potential adverse effects with a proposed checklist is to develop a more realistic picture of the true adverse effects occurring in a given patient while on a specific therapy. It is well known that CGRP is ubiquitous in most tissues throughout the body. In theory, blocking CGRP may carry various risks over time as the block may interfere with the body’s natural protection against cardiovascular and cerebrovascular insults. CGRP also plays an important role in managing stressful conditions. Further, the blood-brain barrier does not protect certain portions of the pituitary and hypothalamus from monoclonals. CGRP is replete throughout the pituitary and hypothalamus. To the authors' knowledge, the mAbs entering the market for migraine prevention have not been evaluated in patients under stress, and there has been no data on the potential effect of CGRP inhibitors on hormones.3

Methods

Population

Patients diagnosed with chronic migraine were assessed after at least 2 months of therapy with a CGRP mAb. The antibodies used included the FDA-approved injectables erenumab (Aimovig), fremanezumab (Ajovy), or galcanezumab (Emgality). (Note that there are also new intravenous and oral delivery products in this class, described on page 53). Many of the patients had trialed two, or all three, of the injectable mAbs. In all, 119 consecutive patients were evaluated, including 89 women and 30 men. Patients’ ages ranged from 20 to 76 years old. All patients had previously utilized a number of preventive medications, typically including onabotulinumtoxinA (Botox) with varying degrees of success. Approximately 60% of the patients were considered to have refractory chronic migraine.

Study Design

This retrospective study covered the time period of October 2018 through January 2020. Patients were seen at the authors’ headache clinic in Illinois. This clinic is an urban, tertiary referral center. The population is socioeconomically diverse. The study was designed to compare methods of data acquisition for adverse effects. All patients provided informed consent, and IRB approval was obtained for this retrospective review.

Data Collection

The authors, who serve as headache specialists in the clinic, as well as a member of the clinic staff, interviewed patients during return office visits. The collected database was free of patient identifiers and names.

There were two parts to this study. First, patients were queried about any adverse effects experienced from mAb use. Specifically, they were asked typical assessment questions: “Have you noticed any side effects from the injections, or have you had any new issues or problems since starting the medication?” Some patients noted a pre-existing problem had worsened since initiating the medication, for instance. If a patient did not identify any adverse effects, the first part of the study was finished. However, if a patient did answer positively about a new adverse effect(s), or an exacerbation of a pre-existing problem, they were asked further questions designed to determine whether the mAb was more likely than not to have caused the new adverse effect.

Following the initial provider–patient questions, patients were then presented with a checklist of possible adverse effects (Part 2). This checklist, outlined below, was meant to capture any additional adverse effects not immediately reported by the patients in Part 1 above.

The checklist, which consisted of 18 medical and psychiatric conditions, was created based on adverse effects that have been attributed to the mAbs. The list was a combination of adverse effects described in the drugs’ published Phase 2 and 3 studies, on the FDA adverse events website, and in post-approval experience (all described below). In addition, sexual dysfunction was included; this particular adverse effect is often not recognized in studies.

Using the checklist, patients were asked to identify only those items which they felt were more likely than not to have resulted from the new medication. In addition, the length of time that the adverse effect lasted was recorded. The potential adverse events were categorized as mild, moderate, or severe. Severity was therefore subjective, and a visual analog scale was not utilized, marking limitations of the study.

The Checklist

The 18 items included in the checklist were defined as follows. Except for the effect of “passing out/loss of consciousness,” patients were asked to circle “mild,” “moderate” or “severe” after each checked item, and to input how long the effect lasted, if at all:

___Anxiety: Have you had (new, or an increase in pre-
existing) excessive worrying, panic, obsessions, or do you feel your body is all “keyed” up?

___Constipation: A significant decrease (new, or exacerbation of pre-existing) in bowel movements, or very hard stools, or consistent difficulty having a bowel movement.

___Depression (a new depression, or a significant exacerbation of a pre-existing one): Feeling down or blue, an increase or decrease in appetite, sleeping problems, loss of desire to interact with people, nothing is fun, less motivated. We will discuss with you the diagnosis of depression.

___Diarrhea: Have you had loose stools or diarrhea (new or worsening of pre-existing) consistently or on a regular basis?

___Faster heartbeat or other chest/heart palpitations/irregular heart rhythms: Have you noticed a (new or exacerbation of pre-existing) significantly faster heartbeat, or palpitations, or irregular heart rhythms?

___Fatigue/Tiredness: New significant fatigue/tiredness or worsening of pre-existing fatigue/tiredness.

___Hair loss: Significant (new) thinning of hair or hair loss; or worsening of pre-existing thinning or loss.

___Increased headache: An increase above your baseline level of headache, that lasted at least 10 days; if your headaches overall are at least 15% worse than before the injections, then it qualifies as increased headache.

___Injection site reactions: After the injection, have you had significant redness, itching, and/or swelling around where you were injected?

___Insomnia: Do you have (new, or worsening of pre-existing) significant trouble going to sleep or staying asleep?

___Irritability: Have you been irritable (new or worsening) since going on the injections, without other causes?

___Joint pain: Joint pains, not just in one area, but in at least two joints, either new or worsening of pre-existing joint pain?

___Muscle pain or cramps: Have you had (new or exacerbation of) muscle aches or cramps, not just in one muscle group but in at least two areas?

___Nausea: Consistent and significant (new or an exacerbation) nausea since the injection.

___Passing out/loss of consciousness: Has this occurred since the injections? How many times? Describe what happened.

___Rash: A rash that began shortly after the injections (with or without itching)?

___Sexual dysfunction: Have you noticed a difficulty with sex, or loss of libido (new or worsening of a pre-existing problem) without another cause?

___Weight gain or loss: Have you gained or lost (not due to dieting) weight since the injections with no other reason?

___Any other side effects: Have you noticed any other new problems, or worsening of pre-existing conditions, that do not have another cause? Which side effect?

Results

Of the 119 patients, 40 (33.6%) did not identify any additional adverse effects with the checklist while 79 patients (66%) did identify additional adverse effects. Table I summarizes the additional adverse effects identified.

Total Self-Reported Adverse Effects

In terms of totals, the number of patients who described additional adverse effects were as follows:

  • 1 additional = 18 patients
  • 2 additional = 15 patients
  • 3 additional = 20 patients
  • 4 additional = 12 patients,
  • 5 to 8 additional =14 patients

Self-Reported Duration of Adverse Effects

Lasted from days to mAb discontinuation:

  • Anxiety (from days to months)
  • Constipation (until the mAb was discontinued)
  • Depression (from weeks to months)
  • Fatigue (from 2 days to months)
  • Hair loss (until the mAb was discontinued)
  • Joint pain (from weeks to months)
  • Irritability (from weeks to months)
  • Sexual dysfunction (until the mAb was discontinued)

     

Lasted days to weeks but did resolve:

  • Diarrhea
  • Muscle cramps
  • Nausea

     

Lasted a specific amount of time:

  • Increased headache: lasted 1 to 15 days
  • Injection site reaction: lasted only a brief period
  • Rash: lasted 47 days for one patient; others reported as lasting 1 to 2 days
  • Weight gain: lasted 1 to 4 months

 

Discussion

Adverse Effects Reported by National Data Collection Systems, Clinicians, and Patients

FDA. FDA’s Adverse Event Reporting System (FAERS) website, as of December 30, 2019, lists 24,643 adverse events attributable to the three migraine preventive CGRP monoclonal antibodies erenumab, fremanezumab, and galcanezumab. Of these, 3,520 events were deemed serious, with some identified as life threatening. There were 126 death cases reported. Erenumab is easily the most widely used CGRP monoclonal, and 18,458 of the 24,643 cases were attributed to erenumab. Fremanezumab had 1,496 adverse events reported, while galcanezumab contributed 4,689 case reports. 4

As the medical community knows, only a small proportion of actual adverse events are reported to FDA. Bearing in mind that these products have been on the market for less than 2 years, these numbers seem staggering. In comparison, Botox, used often for migraine treatment, averages approximately 2,000 reports per year, with few serious issues reported (in the doses used for headache).4

The authors’ clinic has issued prescriptions for the CGRP mAbs to more than 1,300 patients since their 2018 approval.

While efficacy has been reasonable, there have been a multitude of adverse effects. Constipation was reported among more than 20% of our study patients on erenumab (less among the other mAbs). Erenumab's label notes that "serious complications from constipation may occur." For all three of the large CGRP monoclonals, adverse effects have included: worsening headache (6%), depression (4%), nausea (4%), fatigue (4%), joint pain (3%), and hair thinning or loss (3%).2

The authors have witnessed serious adverse effects in four patients (see prior reporting),2,5 including: a 60-year-old woman who had an episode of reversible cerebral vasoconstriction syndrome (which did resolve); a 21-year-old woman (on birth control), with a history of hemiplegic migraine (none since 2015) who suffered a probable migraine-related stroke, with an 80% improvement over 5 months; a 65-year-old woman who described severe fatigue and joint pains which resolved; and a 31-year-old woman who suffered from severe neurologic symptoms, including hemiparesis. The latter patient also described fatigue and joint pain. Work-up was not revealing and she recovered within 2 months.

Quarterwatch: Quarterwatch, a publication of the Institute for Safe Medication Practices (ISMP) that evaluates new medications, has also reviewed the CGRP large monoclonal antibodies approved to date. The publication has focused primarily on erenumab as it is has been on the market longest. Quarterwatch relies on a number of sources, including post-approval studies and FDA reports. ISMP noted in its August 2019 review that a large number of patients experienced adverse events with the CGRPs to date, with constipation being the most prominent. 6

Other adverse effects included hair loss, muscle spasms or cramps, and arthralgias. Anaphylactic shock was recognized in 35 patients. Depression was also listed as a concern. The authors of Quarterwatch state that “depression warrants additional study.” Concerns have also emerged for cardiac events, palpitations, tachycardia, and cardiac arrest. Cases of loss of consciousness were also described. 6

Quarterwatch concluded that “it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.” In addition, they stated that “the long-term effects of blocking all the functions of a highly prevalent signaling molecule remain undetermined.”6

In December 2019, Quarterwatch published on the frequency with which adverse events are reported to FDA, estimating that in general, only 1% of serious adverse effects are actually reported to the agency.7

Anecdotal Comments: In informal discussions with hundreds of headache specialists, a majority have shared with the authors that constipation is an issue for a significant number of their patients. Erenumab causes constipation at an increased rate over the other mAbs according to the data, with one observational study concluding that adverse effects accounted for 33% of discontinuations from erenumab. 7 Clinicians also have shared that the adverse effects seen in their clinical practices seem to outpace those described in the studies.

Patient-driven online chat boards further provide insight into “real world” experience with medications. Many patients state on these boards that they have had excellent results with the mAbs. However, a plethora of adverse events are described as well. The authors have seen at least 400 adverse effect reports on these boards that were felt to be very credible. The most common side effects described have been: fatigue, constipation, hair loss, depression, anxiety, and nausea.

Overall, the adverse effects gleaned from patient comments somewhat match the adverse effect profile reported in the authors' previous studies. They are also similar to those appearing in the FDA FAERS dashboard. 4

Clinical Trials

The Phase 2 and 3 CGRP monoclonal studies may have significantly under-reported adverse effects. Moore, et al, outlines this point in his chapter, “Assessment and Reporting of Harm.”8 It is also well known that trial subjects tend to be healthier, with fewer psychiatric and medical issues, than the patients encountered in pain management offices. 9 Compared to chronic migraineurs, specifically, study patients have often used fewer preventive medications.

Further, the Phase 2 and 3 studies did not appear to include a checklist of various symptoms, to be asked after each treatment visit; instead, participants were asked general questions by the study personnel, which may have led to the under-recognition of side effects. 10

Study Limitations

As noted, this study relied upon patient recollections of adverse effects. It would have been ideal if detailed calendars listing possible adverse effects had been utilized. There was no control group. These patients were relatively refractory, somewhat more than in the typical chronic migraine population. Ascertaining whether the adverse effect was truly due to the monoclonal antibody was somewhat subjective.

Forward Thoughts

This discussion has centered on short-term adverse effects of the injectable CGRP monoclonal antibodies. As headache specialists, the authors are grateful to have these new options to help treat migraine sufferers as the medications have been life-changing for many. However, it will be years before we understand this drug class’s full long-term impact. Clinical studies should include a checklist of probable adverse effects. In addition, a checklist may be helpful in routine clinical practice to assess and monitor patients prescribed these new-class medications.

Overall, the adverse effects gleaned from patient comments somewhat match the adverse effect profile reported in the authors' previous studies.  2 They are also similar to those appearing in the FDA FAERS dashboard.4

Read about the oral gepants, ditan tablet, IV CGRP inhibitors, and more, in New Developments in Migraine Treatment. Plus, see how three clinicians found success using dual therapy (erenumab and onabotulinumtoxin-A) in one refractory migraine patient.

Last updated on: June 18, 2020
Continue Reading:
Erenumab and Onabotulinumtoxin A Show Additive Effect in Refractory Chronic Migraine
close X
SHOW MAIN MENU
SHOW SUB MENU