Intravenous (IV) lidocaine and ketamine infusions could offer relief for inpatients with headache disorders, if they’re willing to bear the potential downsides, Melbourne researchers say.

Their study of 83 patients hospitalised for headache disorders between 2018 and 2021 found IV lidocaine and ketamine helped alleviate pain in nearly half of migraine cases and supported analgesia withdrawal for medication overuse headache. However, the treatment was also associated with prolonged hospital stays and possible side effects, the research team led by Dr Jason Ray, consultant neurologist and headache fellow at the Alfred and Austin hospitals noted.

Patients had previously failed first-line therapies, such as triptans, simple analgesia and prochlorperazine, and while these are “supported by moderate or high-quality evidence” in the emergency department, there are limited second-line treatments with similar backing, they wrote in Frontiers in Neurology.

The study “provides further evidence for the efficacy of [IV] lidocaine and ketamine in inpatient treatment of headache disorders”, they said.

The retrospective study assessed drug efficacy, safety and duration outcomes in 77 patients with migraine, three with new daily persistent headache, two — short-lasting unilateral neuralgiform headache attack with conjunctival injection and tearing and one — cluster headache.

Of lidocaine-treated migraine patients, half (23/45) had ≥ 50% pain reductions over mean 4.5 days, and a third achieved pain freedom by mean 6.2 days. The same goals were met by 34% (11/32) and 16% of those on ketamine within mean 3.4 days and 5.1 days, respectively.

Only 6.7% and 3.1% of lidocaine and ketamine patients returned to hospital within 30 days of discharge, the authors found.

Further, infusion for medication overuse headache allowed analgesia withdrawal in 61% (11/18) of lidocaine and 42% (5/12) of ketamine recipients.

Despite the drugs’ apparent utility, a third of those on lidocaine and 42% on ketamine experienced mostly “minor and not unexpected” adverse effects, including anxiety or agitation, dizziness and paraesthesia. Five lidocaine and four ketamine patients stopped treatment as a result of adverse events.

“Lidocaine and ketamine infusions are an efficacious inpatient treatment for headache disorders, however associated with prolonged length-of-stay and possible side-effects,” the authors wrote of their results.

Though uncertain, IV lidocaine may help relieve headache through its “inhibitory effect on voltage-gated sodium channels” and its active metabolite, monoethylglycine’s inhibition of glycine transporter GlyT1, they suggested.

“In pre-clinical models, GlyT1 inhibition has been shown to reduce allodynia, as well as [normalise] neuronal, voltage-gated sodium channels and c-fiber firing. There is evidence also that lidocaine attenuates IL-6, which has a role in hyperalgesia and allodynia.”

Ketamine is thought to work through “its role as [an] NMDA receptor antagonist. Inhibition of NMDA in turn inhibits glutamate, which has been implicated in cortical spreading depression propagation, central [sensitisation] and activation of nociceptive neurons”, they explained.

While limited by its retrospective nature, their study hinted lidocaine infusions may be more effective than ketamine, as demonstrated by its association with higher mean pain score reduction. Further controlled, prospective studies are needed to confirm this and help guide future treatment decisions.

For now, though, the authors said their study adds evidence “for the use of [IV] lidocaine and ketamine in the treatment of headache disorders”.