Edited by Hannah Stephens, Independent Prescriber - Substance Misuse Services
Promethazine is not a good option to aid sleep quality, especially for people using psychiatric services.
Promethazine was originally used for the management of psychosis, but is now used more widely as an antihistamine, an anti-nausea agent, and sedative. It’s considered a first-generation antihistamine with a strong antagonist affinity to H1 histaminergic receptors, moderate antagonism of muscarinic cholinergic receptors, and weak-moderate affinity to receptors in dopaminergic, adrenergic, serotonergic and glutaminergic systems. Despite being considered an older medication, it’s seen a 50% prescribing increase in English general practice over the last 5 years, with 215,00 prescriptions written in August 2024. This trend is consistent across mental health services, with one London service prescribing 25mg promethazine nocte more frequently than any other non-urgent medication, with a near unanimous indication of ‘for sleep’, potentially due to familiarity of prescribing in psychiatry. Promethazine and diphenhydramine, another first-generation antihistamine are also available over the counter, implying safety of use.
Research shows that sleep and sedation, whilst both reduce states of consciousness are phenomenologically and physiologically distinct, with the latter not achieving the same restorative benefits of natural, human sleep. There is no good quality evidence that promethazine improves sleep quality, and a consensus that H1 antagonism is poorly understood, potentially dependent on other endogenous sedating and wake-promoting systems, and unlikely to yield predictable linear effects, as seen in GABAergic agents such as benzodiazepines and Z-drugs. Promethazine is licenced by MHRA for short-term use in insomnia, however, is not supported by NICE guidelines for insomnia.
In practice, the use of promethazine may prevent engagement with medium-long term psychological and behavioural sleep interventions that have a demonstrated efficacy in improving sleep quality, sustained for years post-intervention. Promethazine also has a long half-life and effect duration of 10-19 hours, leading to hangover states, challenging adherence to consistent waking routines. In the context of addiction, compared to the modern history of benzodiazepine over-prescribing, promethazine may be considered less addictive, however it shares many features with other sedating hypnotics such as tolerance development and withdrawal effects following cessation of use. Furthermore, the recreational use of promethazine is well documented, with established likeability and subsequent street value. It’s known to potentiate the effects of opioids, commonly being used simultaneously with codeine, nick-named ‘Lean’ or ‘Purple Drank’. Side effects of promethazine include QT prolongation, weight gain, nightmares, delirium and anti-cholinergic symptoms, increasing the risk of dementia, and potentially compounding similar side-effects associated with anti-psychotic and other sedative psychotropics. Promethazine is also associated with increased risk of fatality when taken in overdose with other psychiatric medications.
Commentary
The over-prescribing of benzodiazepines and subsequent push to de-prescribe and limit prescribing of these and other hypnotics and sedatives has given rise to the pursuit of effective but less harmful medications to aid and improve sleep. Perhaps this too has driven recreational use of over-the-counter medications, however this review has highlighted the inherent harm of promethazine and other first-generation antihistamines. As these medications are readily available without prescription, individuals may not be aware of the associated risks or could easily minimize the risk compared to other illicit drug or alcohol use. Equally the notion that these medications are sleep promoting suggests perceived benefit and justification of use over potential harms.
As with many psychiatric medications, the risk of QT prolongation may also increase if promethazine is used concurrently with buprenorphine or methadone, necessitating thorough assessment, ECG monitoring and harm reduction advice. Assertive discussions regarding the use of sedating antihistamines at treatment outset may support awareness raising and sleep behaviours. Sleep disturbance is inherent to active substance use, withdrawal, abstinence and psychiatric comorbidities, suggesting the need to proactively embed a behavioural approach to sleep hygiene practices throughout the treatment journey.
Login to view full update