WHO's essential medicines list: Additions for migraine and cluster headache

WHO's essential medicines list (EML) is “the world's most influential list of medicines”; more than 150 countries (three quarters of the world's total) base their own lists upon it (1). Historically, people affected by primary headache disorders have been poorly served by the EML. Until this year, only migraine was featured. Acute treatments were limited to acetylsalicylic acid, paracetamol (acetaminophen) and sumatriptan, with ibuprofen listed only for children. Propranolol was the sole preventative drug.

The EML is reviewed biennially, and, since 2007, additions to it have been an unfulfilled ambition of the Global Campaign against Headache. Opportunity arose when, in 2023, WHO invited Lifting The Burden (LTB) to submit proposals for the 2025 review. LTB asked the International Headache Society to lead the initiative and include the European Headache Federation in a joint working group (the authors). Three meetings were held to decide which drugs were to be proposed for which disorders. Tasks, which included detailed reviews of the evidence supporting each proposal, and cost-effectiveness analyses, were delegated to individual members. Nine proposals were submitted (Table 1), accompanied by letters of support from more than 20 patient or scientific organisations (supplemental material). The overall workload was substantial (2).

Table 1.

Proposed additions to WHO's essential medicines list.

Successful proposals	Unsuccessful proposals
For acute treatment of migraine: ibuprofen (for adults) naproxen (as an alternative to ibuprofen, with better cardiac safety) eletriptan (as an alternative to sumatriptan when this has failed)	For preventative treatment of migraine: amitriptyline bisoprolol (as a better alternative to propranolol) fremanezumab (for frequent or chronic migraine after failure of other options)
Cluster headache as a disorder to be included
For management of cluster headache: sumatriptan subcutaneously (for acute treatment) prednisolone (as bridging therapy) verapamil (for preventative therapy)

Successes

The group sought to add three drugs for acute treatment of migraine, and to include cluster headache among the disorders covered by the list, along with three drugs for its acute and preventative management (Table 1). All of these applications were successful (3–6).

Ibuprofen for acute migraine in adults was not problematic, since it was already on the list for children (LTB's only success in previous applications). Naproxen, several times more costly than ibuprofen, required justifying argument, but it was proposed as an alternative to ibuprofen principally for cardiac safety (7–9). Additional potential benefits were its much longer half-life, and its unique additive effect in terms of sustained pain-free response when used in combination with sumatriptan (10,11). Economic analysis of this combination estimated an incremental cost-effectiveness ratio (extra US$ to be invested per healthy life year [HLY] gained) of US$ 1,026, well below most countries’ willingness-to-pay ceilings. Eletriptan has better efficacy than sumatriptan, but at 13–15 times the cost per treatment success (depending on how this is defined). Eletriptan was proposed as second-line triptan when sumatriptan proved ineffective or was not tolerated. Used thus (i.e., with other options having failed), estimated cost/HLY gained was US$ 5709 with current pricing, also well below usual ceilings. Prices are falling with generic productions.

For cluster headache, the choice of drugs was easy (Table 1), but the proposals were not. The lack of good clinical trials evidence for most candidate drugs, and of sound epidemiological data regarding prevalence, attack frequency and episode duration, were challenging. Economic analyses required multiple assumptions, including assigning a disability weight of 1 (on a 0–1 scale, where 1 represents health loss equivalent to being dead) for the duration of the acute attack. For subcutaneous sumatriptan, estimated cost/HLY gained was US$ 120,623 but, with no patent protection, the price is likely to drop substantially if demand increases through addition to the EML. Applying the current price for Brazil (much lower than elsewhere), estimated cost/HLY gained was US$ 47,892, still above most ceilings. But no other options for acute therapy exist, and this was evidently persuasive. For verapamil, estimated cost/HLY gained was US$ 4163. For prednisolone as bridging therapy, estimated cost/HLY gained was US$ 37,875, but very much reduced with a stopping rule applied (used in all patients initially, but repeated in subsequent cluster periods only in those responding well in the first).

Failures

Both amitriptyline and bisoprolol are on the EML for other indications, and widely available at low cost. Despite limited evidence from clinical trials, which preceded the introduction of modern trials methodology, we believed proposals for both as preventative treatments for migraine would succeed: amitriptyline features in most guidelines, and bisoprolol, as an alternative to propranolol, benefits from a narrower therapeutic dose range, once-daily dosing, better cardioselectivity and minimal lipophilicity. Both were shown to be highly cost-effective, but they were rejected: there was “inadequate evidence for relative benefit compared to currently listed propranolol”. This same argument, applied in previous reviews to sumatriptan versus acetylsalicylic acid, delayed the addition of sumatriptan for several years.

Also rejected was fremanezumab for frequent or chronic migraine (12). All the four marketed monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) have proved superior to placebo in terms of efficacy and have demonstrated good tolerability profiles (13,14), in some cases superior to the traditional oral preventive drugs (15,16). In the absence of head-to-head trials comparing the four monoclonal antibodies targeting CGRP, the choice of fremanezumab was based on the following considerations: i) it is supplied in filled syringes or autoinjectors; ii) it is administered subcutaneously rather than intravenously and, finally iii) the options of monthly or quarterly dosing facilitate refrigerated storage and distribution, and reduce visits if administration by a health-care provider is needed. Evaluation by the UK National Institute for Health and Care Excellence (NICE) had found that fremanezumab, used when other options had failed, was cost-effective at a price of £450 (US$ 584; €541) per monthly 225 mg-injection wherever the willingness-to-pay ceiling was at or above £20,000/HLY gained (US$ 25,970; €24,027) (17). Actual costs of fremanezumab are much lower (about half) now, although highly variable worldwide. WHO's Expert Committee on Selection and Use of Essential Medicines acknowledged the favourable outcomes associated with fremanezumab compared to placebo but did not recommend its inclusion because of absence of the direct comparative evidence versus currently listed propranolol needed to justify the substantial cost difference between these treatments.

Comment

Six successes out of nine applications exemplify what can be achieved when the headache organisations work together. It is, overall, not just a good outcome: it is unusually good for neurological applications, which have faced a high rate of rejection over the past two decades (in contrast, for example, to oncological) (1). The EML serves people with migraine much better now than it has since its inception. The inclusion of cluster headache as a disorder among “priority health-care needs” (2), for which treatments should be made available even in low-resource settings, ought greatly to benefit people with this horrible disorder. Bringing additional medicines into the EML has disproportionate value for those in low- and middle-income countries, encouraging local price negotiations to support inclusion in national lists. Time will tell whether these happen, but WHO's recent report emphasises that headache disorders remain neglected despite the ill health and disability they cause (18). And the rejection of additional preventative drugs for migraine sends a contradictory and wrong message, given the worldwide underuse of these drugs.

The next opportunity for additions will arise in 2027. For those drugs that were rejected this time, the groundwork for re-application is already underway.

Supplemental Material

sj-docx-1-cep-10.1177_03331024261420835 - Supplemental material for WHO's essential medicines list: Additions for migraine and cluster headache

Supplemental material, sj-docx-1-cep-10.1177_03331024261420835 for WHO's essential medicines list: Additions for migraine and cluster headache by Cristina Tassorelli, Christian Lampl, Massimo Leone, Antoinette MaassenVanDenBrink, Mario FP Peres, Patricia Pozo-Rosich, Francesca Puledda, Simona Sacco, Michela Tinelli, Derya Uludüz and Timothy J Steiner in Cephalalgia