Different Routes of Administration in Chronic Migraine Prevention Lead to Different Placebo Responses

A Meta-analysis

Diego Belandrino Swerts; Fabrizio Benedetti; Mario Fernando Prieto Peres

Pain. 2022;163(3):415-424.

Abstract and Introduction

Abstract

Placebo response is a powerful determinant of health outcomes in several disorders. Meta-analysis of clinical trials in pain conditions shows that it can contribute up to 75% of the overall treatment effect. Placebo response deriving from different routes of administration is poorly understood in primary headaches' pharmacological prevention. Thus, this meta-analysis aims to analyze how different routes of administration affect the placebo response in chronic migraine (CM). We conducted a meta-analysis with 7 randomized, double-blind, placebo-controlled clinical trials, with 5672 patients older than 18 years who suffer from CM without associated comorbidities. We compared those who received a placebo-administered agent for the preventive treatment of CM subcutaneous, endovenous, or oral against those who received multiple head injections. The primary outcome was reduction in the number of days with migraine in the month assessed at 12, 16, and 24 weeks of treatment compared with baseline. Our study shows that placebo responses were greater when botulinum toxin was applied to the head, followed by intravenous injection of the anti-calcitonin gene-related peptide monoclonal antibody eptinezumab. Oral topiramate and subcutaneous monoclonal showed no difference, being inferior to head injection. Administration route affects placebo responses in CM preventive treatment. Elucidating the underlying mechanisms that mediate a placebo response in migraine treatment is beneficial to clinical practice and drug development, especially when comparing drugs with different routes of administration, with the effect of application to the head being superior to the other routes in this study. In our study the placebo response accounted for approximately 75% of the therapeutic gain in the treatment of CM.

Introduction

Chronic migraine (CM) is a debilitating neurological condition, estimated to affect 2% of the world population.^[29] It is defined as a headache occurring on 15 or more days/month for more than 3 months.^[9] Chronic migraine therapeutic approach is more complex than episodic migraine.^[8,16,17] Comorbid conditions are common, particularly psychiatric and sleep disorders,^[22,28] with significant reduction in quality of life^[35] and frequent analgesic use. Patients often need a multifactorial approach, adding pharmacological treatments to nonpharmacological options.

Placebo response is a powerful determinant of health outcomes in several disorders and may directly interfere with tolerance and efficacy of pharmacological therapy.^[1,2] High-evidence studies have demonstrated the importance of placebo and nocebo effects, with symptom relief in conditions such as pain, depression, Parkinson disease, hypertension, arthritis, migraine, cancer, and asthma.^[20] This result reaches 75% of the overall treatment in conditions such as fibromyalgia^[37] and osteoarthritis.^[38] In the management of acute headache, these results ranged between 21% and 30% of remission with placebo.^[25,26,30]

In a consensus of experts in placebo and nocebo,^[13] the importance of differentiating between the placebo effect and the placebo response^[14] was emphasized. The placebo response includes all health changes that result after the application of an inactive treatment, whereas the placebo effect refers to changes specifically attributable to the placebo mechanism, including patient's expectation, genetics, disease severity, patient–physician relationship, environmental circumstances, and external factors such as the route of administration and treatment aggressiveness.^[24]

Previous studies show that different routes of administration and placebo procedures result in different outcomes. Intra-articular and topical placebo had a significantly greater response than oral placebo in osteoarthritis.^[5] Pain threshold was not different in an experiment comparing placebo pills, sham acupuncture, and cue conditioning.^[21] In high-altitude headache, placebo oxygen inhaled through a mask was superior to placebo aspirin pills.^[6]

In migraine, subcutaneous placebo was superior to the oral route,^[9,26] another meta-analysis showed greater effect with intranasal route,^[30] and finally sham acupuncture surgery and sham surgery had more pronounced reduction of migraine frequency than oral placebos.^[27]

Such studies corroborate the hypothesis that a good part of the clinical treatment of migraine might be due to nonspecific effects and that the size of such effects might differ between different routes of administration. Therefore, we aim to answer the question: Do different routes of administration have different placebo effects in migraine?

Chronic migraine is a good model for studying placebo response. It is a well-defined disease, affects a large population, and a great number of clinical trials have been performed. We aimed to estimate the difference between placebo response in application on specific areas in the head and neck (botulinum toxin)^[3,4,12] vs administered orally (topiramate),^[33] intravenous (eptinezumab),^[23,31] and subcutaneous (erenumab,^[36] galcanezumab,^[11,15] and fremanezumab)^[7,32] in CM preventive treatment, by collecting data from completed randomized double-blind placebo-controlled trials in adults. This knowledge would benefit both clinical practice and drug development.

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Abstract and Introduction
Methods
Results
Discussion
Conclusion
References
Appendix

Table 1. Description of PICO components of systematic review.
P	Men and women older than 18 years who suffer from chronic migraine (more than 15 migraine episodes per month from 3 months) without associated comorbidities
I	Placebo-administered agent for preventive treatment of chronic migraine
C	Placebo agent administered according to the PREEMPT protocol
O	Reduction in the number of days with migraine in the month accessed at 12, 16, or 24 weeks of treatment compared with baseline

Table 2. Characteristics included studies.
Studies	Year	Country	Population	Participant	Method	Intervention	Results
PREEMPT1	2010	North America sites	Men or women aged 18–65 years with a history of CM meeting the diagnostic criteria listed in ICHD-II, with the exception of complicated migraine (hemiplegic migraine, basilar-type migraine, ophthalmoplegic migraine, and migrainous infarction) were eligible.	Onabotulinumtoxin A (n 341) Mean age 41.2 Placebo (n 332) Mean age 42.1	24-week, double-blind, parallel group, placebo-controlled phase.	Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxin A (155-195 U) or placebo (2 cycles)	The study showed a greater reduction in MHDs in the intervention group (−7.6 onabotulinumtoxinA vs −6.1 placebo P = 0.002, 95% CI −1.5 (−2.6 to 0.59))
PREEMPT2	2010	66 Global sites (50 North America and 16 European)	Men or women aged 18–65 years with a history of CM meeting the diagnostic criteria listed in ICHD-II, with the exception of complicated migraine (hemiplegic migraine, basilar type migraine, ophthalmoplegic migraine, migraineurs infarction) were eligible	Onabotulinumtoxin A (n 347) Mean age 41 Placebo (n 358) Mean age 40.9	24-week, phase 3, double-blind, parallel group, placebo-controlled phase.	Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxin A (155–195 U) or placebo (2 cycles)	The study showed a greater reduction in MHDs in the intervention group (−8.7 days onabotulinumtoxinA vs −6.3 placebo, P < 0.01, 95% CI −2.4 (−3.31 to −1.36))
Epitnezumab (PROMISE-2)	2020	128 sites in 13 countries (USA, Spain, Ukraine, Russia, United Kingdom, Republic of Georgia, Hungary, Italy, Slovakia, Germany, Czech Republic, Denmark, and Belgium)	Adults 18–65 years, with a diagnosis of CM at or before 50 years of age were eligible for participation if they had a history of CM for ≥12 months before screening and experienced ≥ 15 to ≤ 26 headache days and ≥ 8 migraine during the 28-day screening period.	Eptinezumab 100 mg (n 356) Mean age 41.0 Epitinezumab 300 mg (n 350) Mean age 41.0 Placebo (n 366) Mean age 39.6	Phase 3, multicenter, randomized double-blind, parallel group, placebo-controlled phase. The primary endpoint was change from baseline in MMDs over wk 1 to 12	Subjects were randomized to receive eptinezumab 100, 300 mg, or placebo (1:1:1) administered on day 0 and week 12.	Epitinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1 to 12 compared with placebo (placebo −5.6, 100 mg −7.7, P < 0.01 vs placebo; 300 mg – 8.2, P < 0.01 vs placebo)
Erenumab	2017	69 headache and clinical research centers in North America (Canada and USA) and Europe (Czech Republic, Denmark, Finland, Germany, Norway, Poland, Sweden, and United Kingdom)	Men or women aged 18–65 years with a history of CM (with or without aura). Patient had to have migraine for 15 or more days per month, or 8 or more of those days were migraine days	Erenumab 70 mg (n 191) Mean age 41.4 Erenumab 140 mg (n 190) Mean age 42.9 Placebo (n 286) Mean age 42.1	Phase 2, multicenter, randomized double-blind, parallel group, placebo-controlled phase. The primary endpoint was change from baseline in MMDs over weeks 1 to 12	Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70 mg, or erenumab 140 mg	Erenumab 70 and 140 mg reduce MMDs vs placebo (both doses −6.6 days vs placebo −4.2 days, difference −2.5, P < 0.01, 95% CI (−3.5 to −1.4)
Galcanezumab (REGAIN)	2018	116 headache and clinical research in 12 countries (Argentina, Canada, Czech Republic, Germany, Israel, Italy, Mexico, the Netherlands, Spain, Taiwan, United Kingdom, and USA)	Adults 18–65 years with CM meeting the diagnostic criteria listed in ICHD-II. The continuation or start of any additional migraine preventive treatment was not permitted	Galcanezumab 120 mg (n 278) Mean age 39.6 Galcanezumab 240 mg (n 277) Mean age 41.05 Placebo (n 555) Mean age 41.5	Phase 3, multicenter, randomized double-blind, parallel group, placebo-controlled phase with 12 weeks.	Randomized in a 1:1:2 ratio received a subcutaneous injection of galcanezumab 120 mg/month (after an initial loan of 240 mg) or 240 mg/month or placebo	Both galcanezumab groups demonstrated a greater reduction in MHDs compared with placebo (P < 0.001; placebo −2.7; galcanezumab 120 mg −4.8; 240 mg −4.6)
Fremanezumab	2017	132 sites in 9 countries	Adults 18–70 years with CM meeting the diagnostic criteria listed in ICHD-II.	Fremanezumab quarterly (n 376) Mean age 42.0 Fremanezumab monthly (n 379) Mean age 40.6 Placebo (n 375) Mean age 41.4	Randomized double-blind, placebo-controlled phase with a screening visit, a 28-day preintervention period and a 12-week intervention period	Randomized in a ratio 1:1:1 to receive fremanezumab quarterly (a single dose 675 mg at baseline and placebo at week 4 and 8), fremanezumab monthly (625 mg at baseline and 225 mg at week 4 and 8) or matching placebo	There was a reduction in the average number of monthly MHDs with fremanezumab quarterly (4.9 days) and fremanezumab monthly (5.0) superior than with placebo (3.2) (P > 0.001 in both comparisons)
Topiramate	2007	46 U.S. sites	Adults 18–65 years with 15 or more headache days per month, at least half of those were migraine/migrainous headaches	Topiramate 100 mg (153) Mean age 37.8 Placebo (n 153) Mean age 38.6	Randomized double-blind, placebo-controlled, multicenter study with 16 weeks of treatment	Randomized 1:1 to receive topiramate 100 mg or placebo. An initial dose of topiramate 25 mg/d was titulated upward in weekly increments of 25 mg/d to a maximum 100 mg/d (or to the maximum tolerated dose)	Topiramate treatment results in a statistically significant mean reduction of migraine and reduction of MHDs relative to baseline (topiramate −5.6 vs placebo −4.1; P = 0.032)

CI, confidence interval; CM, chronic migraine.

Table 3. Baseline and duration of Included studies.
Trials	Year	Phase	Duration (wk)	Baseline monthly migraine days placebo	Baseline monthly migraine days intervention
PREEMPT 1	2010	Phase 3	24	19.1 (4.1)	19.1 (4.0)
PREEMPT 2	2010	Phase 3	24	18.7 (4.1)	19.2 (3.9)
Eptinezumab (Promise-2)	2020	Phase 3	12, 24	16.2 (4.6)	16.1 (4.6)//16.1 (4.8)
Erenumab	2017	Phase 2	12	18.2 (4.7)	17.9 (4.4)//17.8 (4.7)
Galcanezumab (REGAIN)	2018	Phase 3	12	19.6 (4.6)	19.4 (4.3)//19.2 (4.6)
Fremanezumab	2017	Phase 3	12	16.2 (4.9)	16 (5.2)//16.4 (5.2)
Topiramate	2007	Phase 3	16	15.1 (5.8)	15.2 (6.4)

Data are mean (SD). In the intervention, we have the baseline in the different doses of medications. Epitnezumab 10//300 mg. Erenumab 70//140 mg. Galcanezumab 120//240 mg. Fremanezumab monthly//quarterly.

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Different Routes of Administration in Chronic Migraine Prevention Lead to Different Placebo Responses

A Meta-analysis

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

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