This review (s=9, 2022) analyses retrospective surveys that quantified the self-reported efficacy of two or more cluster headache (CH) treatments. The consistently reported efficacy of psilocybin and LSD in prophylactic treatment indicates the need for clinical studies in this area.

Abstract

“Purpose of Review: The use and efficacy of various substances in the treatment of CH have been studied in several retrospective surveys. The aim of the study is to systematically review published survey studies to evaluate the reported efficacies of both established and unconventional substances in the abortive and prophylactic treatment of both episodic and chronic CH, specifically assessing the consistency of the results.

Recent Findings: No systematic review have been conducted of these studies previously. A systematic literature search with a set of search terms was conducted on PubMed. Retrospective surveys that quantified the self-reported efficacy of two or more CH treatments, published in English during 2000–2020, were included. Several key characteristics and results of the studies were extracted. A total of 994 articles were identified of which 9 were found to be eligible based on the selection criteria. In total, 5419 respondents were included. Oxygen and subcutaneous triptan injections were most reported as effective abortive treatments, while psilocybin and lysergic acid diethylamide were most commonly reported as effective prophylactic treatments. The reported efficacy of most substances was consistent across different studies, and there were marked differences in the reported efficacies of different substances. The reported order of efficacy is generally in agreement with clinical studies. The findings suggest that retrospective surveys can be used to obtain supporting information on the effects of various substances used in the treatment of CH and to form hypotheses about novel treatment methods. The consistently reported efficacy of psilocybin and LSD in prophylactic treatment indicates the need for clinical studies.

Authors: Sakari Rusanen, Suchetana De, Emmanuelle A. D. Schindler, Ville Artto & Markus Storvik

Summary

This study systematically reviewed published survey studies to evaluate the reported efficacies of various substances in the treatment of CH.

A systematic review of retrospective surveys was conducted on PubMed to determine the efficacy of various substances used in the treatment of CH. Oxygen and subcutaneous triptan injections were most commonly reported as effective abortive treatments, while psilocybin and lysergic acid diethylamide were most commonly reported as effective prophylactic treatments.

Background

Cluster headache (CH) is a disorder of the trigeminal autonomic cephalalgia, characterized by extremely severe unilateral headaches that strike several times a day, often at precise times, accompanied by ipsilateral autonomic symptoms. There are acute and preventive treatments, as well as transitional (or interim) bridge treatments.

Triptans, high-flow oxygen inhaled through a non-rebreather mask, intranasal lidocaine, cocaine and dihydroergotamine sprays, subcutaneous octreotide, and intravenous somatostatin are recommended as the first-line options for acute treatment. There is limited clinical evidence for the efficacy of preventive medication.

In transitional treatment, oral regimens of corticosteroids, local corticosteroid injections near the greater occipital nerve, or intravenous dihydroergotamine have shown some effectiveness. Neuromodulatory treatments can also be attempted in certain treatment-resistant patient groups.

An estimated one-third of CH patients use complementary or alternative treatment methods in addition to conventional treatments. These methods are often illicit and have not been clinically studied.

Prospective clinical studies use symptom diaries and other patient reports to evaluate CH treatments. Retrospective surveys can be used to compare self-reported efficacy of treatment options over a long period of time in large patient samples.

Objective

Several retrospective surveys have been conducted to evaluate the use and self-reported efficacy of various established medications and unconventional substances in abortive and prophylactic treatments of CH. The results of these surveys are generally consistent with the findings of randomized controlled trials.

Selection of the Studies

A PubMed search was conducted in May 2020 and December 2020 using the developed search terms. The selected studies were done in collaboration with an information specialist.

A total of 994 articles were found using the search function, and only articles quantifying the reported effects of two or more substances were included in the review.

PubMed was used to complement the search for studies, and the reference lists of the found survey articles were reviewed to find similar studies. However, no additional studies were identified through the complementary search methods.

Data Collection

Two authors independently read through each of the selected surveys several times to identify factors that might have biased the results. They also extracted demographic and other characteristics of the participants and the self-reported abortive and prophylactic efficacy of established and unconventional treatments across different surveys.

Data Synthesis and Analysis

Data concerning self-reported efficacies for acute or abortive treatments were first combined in one table, and data concerning preventive or prophylactic treatments were combined into another table. The scales used to measure efficacy were not the same in all articles.

The self-reported efficacy of the treatments was explored with a standard data-driven hierarchical clustering and visualized as heatmap and dendrogram using the Heatmapper-tool implemented over R.

Characteristics of the Survey Studies and the Respondents

The characteristics of the survey studies are summarized in Tables 2 and 3, and all of them used a structured questionnaire with closed-ended or multiple-choice questions providing specific response options to choose from. The data collection method was mostly web-based (7 out of 9 surveys).

5419 respondents were included in the studies, with the average age being 40 – 50 years old. The majority of respondents were of European descent from Europe or North America, and the ratio of CCH patients to ECH patients varied between 0.47 and 1.16.

Assessment of CH Treatments in the Survey Studies

In nine studies, the efficacy of conventional and unconventional treatments was asked, and the results were presented in parallel. Two studies specifically asked about the duration and frequency of symptoms, while the others only asked about the general effects on the symptoms.

Eight studies were included in this review. The scales used to collect and analyze data on treatment efficacy varied in the number of options and words expressing the levels of the scales. Another study [30] had a three-level scale of “effective”, “partially effective” and “ineffective” options, but the “partially effective” option was omitted from the hierarchical clustering to avoid artifacts.

Self‑Reported Efficacy of the Surveyed CH Treatments

The reported efficacies of different treatment substances are generally consistent across the different studies, with oxygen, triptans, and psilocybin belonging to the same clade. Melatonin, valproic acid, gabapentin, and especially amitriptyline and propranolol, belong to the clade of treatments with low self-reported efficacy.

All the above-mentioned directly acting serotonergic substances were reported to be more effective than verapamil and even corticosteroids, and psilocybin mushrooms were reported to have an abortive efficacy comparable to oxygen and subcutaneous triptan injections.

In the survey by Sewell et al. [30], verapamil and lithium were underperforming compared to the rest of the treatments, but if they had been assigned to the “effective” category, the results would have matched exactly with the results from other surveys.

Discussion

The results of this review show that psilocybin mushrooms and LSD are the most effective prophylactic treatments in CH, and combining data from multiple survey studies can provide important and reliable information.

Consistency Between the Survey Results and Close Agreement with the Clinical Data

There was overall good consistency in the reported efficacies across the 8 surveys, despite methodological differences. Oxygen, triptans, verapamil, and corticosteroids were found to be the most effective CH treatments, and injectable sumatriptan was consistently reported more effective than orally or nasally administered triptans.

High Self‑Reported Efficacy of Psilocybin and LSD in the Prophylactic Treatment of CH

A theme detected in our results is the consistently self-reported high efficacy of psilocybin mushrooms and LSD as preventive treatments for migraine. This result is echoed in other studies and reports, but the number of respondents was small.

LSD and psilocybin are both active in central serotonin 2A (5HT-2A) receptors, and psilocybin resembles triptans structurally. Psilocybin is most commonly consumed in the form of psilocybin mushrooms.

Biases in the Survey Studies

Survey studies are prone to several biases, which can be assessed based on the extracted variables presented in the results section. The surveys were retrospective, open for anyone to respond to, and most were online questionnaires.

Petersen et al. [37] listed patient support groups as a source of recruiting respondents, making the rest of the surveys depend upon the veracity of the respondents.

The survey respondents were not entirely representative of the wider CH population. They had a higher ratio of CCH to ECH patients, and were more interested in contributing to the CH related research.

This review found that the results are most consistent when using similar binary scales. The results are inconsistent when using a three-level scale, however, because the “effective” category is very strict and the “partially effective” category is similar to the “responder” category.

Strengths and Limitations of Combining Survey Data

The results of surveys collected from multiple locations, populations, and methods should be analyzed together to increase the value of the surveys. However, there is no standard method for combining their results.

Multiple reasoning strategies were used to elaborate the strengths and weaknesses of our results. Oxygen was found to be the most effective conventional abortive treatment, and LSD and psilocybin mushrooms were found to be effective in self-treatment.

The results suggest that psilocybin, LSD, ergolines, and triptans, all have similar serotonergic mechanisms of action, and can be used to prevent CH attacks. The first RCT of psilocybin in CH has completed, and the report is pending.

The review of surveys did not consider biological gradients, dose-responses, or specificity of outcome variable, nor did it report direct comparisons between two or more treatments.

A valid analogy of an unconventional self-treatment becoming accepted and even recommended as a first-line treatment for CH is oxygen, which was serendipitously discovered and has been used as a self-treatment for CH since the 1930s.

Future Considerations

Future survey studies should utilize random sampling, target different ethnic groups, identify the respondents, verify their diagnosis, measure adverse effects, and ask the participant to directly compare the self-reported efficacy between any two treatments.

Relevance in Clinical Practice

This review highlighted that many patient groups endorse complementary or alternative treatments for CH, and that some patients use them in self-treatment. Physicians should be aware of the possible harms and benefits of these treatments, and should evaluate contraindications and interactions with the patients.

Conclusions

In this systematic review of retrospective survey studies on CH treatment efficacy, we observed consistency in the reported efficacy of most treatments and consistent differences between the reported efficacies of different substances used for CH treatment.

This review indicates that psilocybin mushroom and LSD have a high self-reported efficacy in the treatment of CH, despite the social taboo and legal sanctions attached with their use.