What drugs work for NDPH?
TLDR: We don't know as NDPH might have different causes for different people, but below are the most commonly tried and their intended mechanism
New daily persistent headache (NDPH) is defined by how it starts (a daily headache from a clearly remembered day) rather than by a known mechanism. If you are new to the condition, the complete patient guide to NDPH covers diagnosis, causes and the NHS route in full. This piece is narrower: it looks only at the drugs.
The official ICHD-3 diagnostic criteria are:
- A: Persistent headache fulfilling criteria B and C.
- B: A distinct and clearly remembered onset, with the pain becoming continuous and unremitting within 24 hours of starting.
- C: Present for more than 3 months.
- D: Not better accounted for by another ICHD-3 diagnosis.
As such, it is more a diagnosis of exclusion than one of a defined mechanism. In the UK at least, no drug is licensed for NDPH itself, so doctors usually borrow treatments from migraine or tension-type headache, depending on which one the person’s headache most resembles.
This article sets out the potential medications available to try and support management of NDPH. Note that I am not a clinician. I’m a patient with new daily persistent headache. I woke up on 23rd December 2022, previously fit and healthy, with a headache on the right side of my forehead, a headache I’ve had ever since. The full timeline is elsewhere on this site.
This is just my reading of the evidence and intended to help you understand the symptoms and the condition better.
The drugs most likely to be offered
- Amitriptyline is perhaps the most likely drug to be prescribed in the UK for NDPH. As I understand it, amitriptyline blocks the reuptake of serotonin and noradrenaline, which strengthens the brainstem pathways that suppress pain signals in the spinal cord. In plain language, the body has a “volume knob” for pain. Amitriptyline turns that knob down by leaving more of the brain’s natural pain-dampening chemicals in circulation.
- Propranolol is a beta-blocker. I don’t think its mechanism is actually settled. I think the leading idea is that it blunts the effect of adrenaline, which makes our brains less susceptible to cortical spreading depression, which makes it harder to tip the brain into a headache state. As such, I think it’s more commonly prescribed for episodic migraine than persistent headache.
- Candesartan’s mechanism is also unclear, but the likely mechanism is that it blocks angiotensin II type 1 receptors. These receptors can make nerves and blood vessels more reactive. Blocking them might settle the system down and reduce inflammation.
- Pizotifen blocks serotonin 5-HT2 receptors and histamine receptors, which may reduce serotonin-driven sensitisation of pain pathways. Serotonin acts as a messenger in headache circuits. Pizotifen stops some of those messages being received, so the pain system is less easily switched on.
- I know less about topiramate, but my understanding is that it aims to calm overactive nerve cells.
Other options which can be explored include CGRP-targeted drugs, botulinum toxin, nerve blocks or gabapentinoids.
I have written separately about the first three in more depth, including what they do to blood pressure and heart rate if you also have autonomic symptoms, in the amitriptyline, propranolol and candesartan evidence review. The non-prescription options that headache clinics tend to suggest alongside these are covered in supplements for chronic headache prevention.
Summary table
| Group | Drug | Scientific mechanism | Plain terms | Where it mainly acts |
|---|---|---|---|---|
| Central pain modulation | Amitriptyline | Blocks serotonin and noradrenaline reuptake; also blocks sodium channels and NMDA receptors | Turns down the body’s pain “volume knob” | Brain and spinal cord |
| Venlafaxine, duloxetine | Blocks serotonin and noradrenaline reuptake | Same volume knob, usually fewer side effects | Brain and spinal cord | |
| General stabilisers | Propranolol | Blocks beta-adrenergic receptors; lowers thalamocortical excitability and spreading depression | Blunts adrenaline, makes the brain less “twitchy” | Brain (mechanism uncertain) |
| Candesartan | Blocks angiotensin II type 1 receptors; affects sympathetic tone and inflammation | Blocks a hormone that makes nerves and vessels reactive | Brain and blood vessels (uncertain) | |
| Pizotifen | Blocks 5-HT2 serotonin and histamine receptors | Stops some serotonin “messages” being received | Brain | |
| Flunarizine | Blocks calcium channels | Reduces nerve cell overactivity | Brain | |
| Ion channel calmers | Topiramate | Blocks sodium channels and glutamate receptors; enhances GABA | Presses the brake, eases off the accelerator | Brain |
| Gabapentin, pregabalin | Binds α2δ calcium channel subunit, reducing neurotransmitter release | Quietens nerves firing too readily | Brain and spinal cord | |
| CGRP pathway | Erenumab | Antibody blocking the CGRP receptor | Blocks where the pain molecule docks | Outside the brain, trigeminal system |
| Fremanezumab, galcanezumab, eptinezumab | Antibodies binding CGRP itself | Mops up the pain molecule | Outside the brain, trigeminal system | |
| Atogepant, rimegepant | Small-molecule CGRP receptor blockers | Same target, as tablets | Mostly outside the brain | |
| Nerve ending blockers | Botulinum toxin A | Stops release of CGRP, substance P and glutamate from sensory nerve endings | Stops nerve endings releasing pain chemicals | Nerves in the head and neck |
| Occipital nerve block | Local anaesthetic (± steroid) at the trigeminocervical relay | Numbs a junction box to reset the circuit | Base of the skull |
How the groups differ
- Breadth: the first three groups act broadly on the central nervous system. The last two target the head’s own pain machinery quite specifically.
- Headache type: central pain modulators suit both migraine-like and tension-type pain. The CGRP drugs and botulinum toxin are migraine-specific.
Assessing efficacy is tricky
Most of the evidence comes from migraine. Almost every preventive in the table was tested in migraine trials, so using them for NDPH means assuming NDPH behaves like migraine. For the NDPH subset that looks migrainous, that assumption is reasonable. The rest of the NDPH evidence is thin. It consists mainly of small retrospective case series from specialist headache centres, with no large randomised trials. Those centres also see the most treatment-resistant patients, so their results may understate how well treatments work in NDPH more broadly.
The causes are probably varied. Reported triggers include infection, stressful life events and surgery, and some cases have no clear trigger at all. Because NDPH is defined by how it starts rather than by what drives it, the label probably groups together several different underlying processes. That makes a single “best performer” unlikely. A drug could work well for one subgroup and look ineffective when everyone is pooled together. The patient guide goes into the argument that NDPH is a syndrome rather than a single disease.
NHS access
On NHS access, NICE criteria for CGRP antibodies and botulinum toxin require a chronic migraine diagnosis plus three failed preventives.
Whether the headache is classed as migrainous NDPH or chronic migraine may affect eligibility (and suitability of treatment), which makes it important to raise with your doctor. Keeping a clear record of what you have tried, at what dose, for how long, and why it stopped is what unlocks the next step; preparing for a GP appointment and what I wish I’d known earlier cover how to do that.
Ideally, clinicians will usually treat by phenotype, choosing drugs according to whether the headache looks more like migraine or more like tension-type headache, and then work through the options by trial and error. It’s a pragmatic approach rather than a mechanism-guided one. It will stay that way until research separates NDPH into subgroups with identifiable causes.
References
International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. Section 4.10.
Robbins MS, Grosberg BM, Napchan U, Crystal SC, Lipton RB. Clinical and prognostic subforms of new daily-persistent headache. Neurology. 2010;74(17):1358–1364.
Yamani N, Olesen J. New daily persistent headache: a systematic review on an enigmatic disorder. J Headache Pain. 2019;20(1):80.
Peng KP, Rozen TD. Update in the understanding of new daily persistent headache. Cephalalgia. 2023;43(1):03331024221146314.
National Institute for Health and Care Excellence. Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. Technology Appraisal Guidance TA260. 2012.
National Institute for Health and Care Excellence. Erenumab for preventing migraine. TA682. 2021. Fremanezumab for preventing migraine. TA764. 2022. Galcanezumab for preventing migraine. TA659. 2020. Eptinezumab for preventing migraine. TA871. 2023.