Medicines associated with dependence or withdrawal: a mixed-methods public health review and national database study in England
Open accessAbstract
BACKGROUND: Antidepressants, opioids for non-cancer pain, gabapentinoids (gabapentin and pregabalin), benzodiazepines, and Z-drugs (zopiclone, zaleplon, and zolpidem) are commonly prescribed medicine classes associated with a risk of dependence or withdrawal. We aimed to review the evidence for these harms and estimate the prevalence of dispensed prescriptions, their geographical distribution, and duration of continuous receipt using all patient-linked prescription data in England. METHODS: This was a mixed-methods public health review, comprising a rapid evidence assessment of articles (Jan 1, 2008, to Oct 3, 2018; with searches of MEDLINE, Embase, and PsycINFO, and the Cochrane and King's Fund libraries), an open call-for-evidence on patient experience and service evaluations, and a retrospective, patient-linked analysis of the National Health Service (NHS) Business Services Authority prescription database (April 1, 2015, to March 30, 2018) for all adults aged 18 years and over. Indirectly (sex and age) standardised rates (ISRs) were computed for all 195 NHS Clinical Commissioning Groups in England, containing 7821 general practices for the geographical analysis. We used publicly available mid-year (June 30) data on the resident adult population and investigated deprivation using the English Indices of Multiple Deprivation (IMD) quintiles (quintile 1 least deprived, quintile 5 most deprived), with each patient assigned to the IMD quintile score of their general practitioner's practice for each year. Statistical modelling (adjusted incident rate ratios [IRRs]) of the number of patients who had a prescription dispensed for each medicine class, and the number of patients in receipt of a prescription for at least 12 months, was done by sex, age group, and IMD quintile. FINDINGS: 77 articles on the five medicine classes were identified from the literature search and call-for-evidence. 17 randomised placebo-controlled trials (6729 participants) reported antidepressant-associated withdrawal symptoms. Almost all studies were rated of very low, low, or moderate quality. The focus of qualitative and other reports was on patients' experiences of long-term antidepressant use, and typically sudden onset, severe, and protracted withdrawal symptoms when medication was stopped. Between April 1, 2017, and March 31, 2018, 11·53 million individuals (26·3% of residents in England) had a prescription dispensed for at least one medicine class: antidepressants (7·26 million [16·6%]), opioids (5·61 million [12·8%]), gabapentinoids (1·46 million [3·3%]), benzodiazepines (1·35 million [3·1%]), and Z-drugs (0·99 million [2·3%]). For three of these medicine classes, more people had a prescription dispensed in areas of higher deprivation, with adjusted IRRs (referenced to quintile 1) ranging from 1·10 to 1·24 for antidepressants, 1·20 to 1·85 for opioids, and 1·21 to 1·85 for gabapentinoids across quintiles, and higher ISRs generally concentrated in the north and east of England. In contrast, the highest ISRs for benzodiazepines and Z-drugs were generally in the southwest, southeast, and east of England, with low ISRs in the north. Z-drugs were associated with increased deprivation, but only at the highest quintile (adjusted IRR 1·11 [95% CI 1·01-1·22]). For benzodiazepines, prescribing was reduced for people in quintiles 4 (0·90 [0·85-0·96]) and 5 (0·89 [0·82-0·97]). In March, 2018, for each of medicine class, about 50% of patients who had a prescription dispensed had done so continuously for at least 12 months, with the highest ISRs in the north and east. Long-term prescribing was associated with a gradient of increased deprivation. INTERPRETATION: In 1 year over a quarter of the adult population in England had a prescription dispensed for antidepressants, opioids (for non-cancer pain), gabapentinoids, benzodiazepines, or Z-drugs. Long-term (>12 months) prescribing is common, despite being either not recommended by clinical guidelines or of doubtful efficacy in many cases. Enhanced national and local monitoring, better guidance for personalised care, and better doctor-patient decision making are needed. FUNDING: Public Health England.
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Treatments targeted at insomnia may improve and prevent depression.
“and treatments targeted at insomnia may improve 499 and prevent depression. 500”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [499]
Antidepressants do not differ from other dependence-forming CNS drugs like benzodiazepines, opioids, gabapentinoids, or psychostimulants in their propensity to cause dependence and withdrawal.
“In this respect, antidepressants do not differ from other dependence-forming central nervous system (CNS) drugs like benzodiazepines, opioids, gabapentinoids, or psychostimulants.3,19–22”
From Protracted withdrawal syndrome after stopping antidepressants: a descriptive quantitative analysis of consumer narratives from a large internet forum (2020) · cites this paper as [3]
Pregabalin and gabapentin have been clearly identified as possessing a distinct potential for misuse.
“Following initial reports from this Journal (53) the gabapentinoids pregabalin and gabapentin have been clearly identified as possessing a distinct potential for misuse (54).”
From Coming Off Prescribed Psychotropic Medications: Insights from Their Use as Recreational Drugs (2020) · cites this paper as [54]
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- Authors
- Marsden, J., White, M., Annand, F., Burkinshaw, P., Carville, S., Eastwood, B., Kelleher, M., Knight, J., O'Connor, R., Tran, A., Willey, P., Greaves, F., & Taylor, S.
- Affiliations
- King's College London (GB)
- Public Health England (GB)
- Royal College of Physicians (GB)
- South London and Maudsley NHS Foundation Trust (GB)
- Corresponding author
- Marsden, John
- ORCID
- Venue
- The Lancet Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 6
- Issue
- 11
- Pages
- 935-950
- ISSN
- 2215-0366 (ISSN-L)
- PMC
- PMC7029276
- OpenAlex
- W2978303387
- Cited by
- 106
- References
- 40
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 15 · 2023: 15 · 2022: 18 · 2021: 18 · 2020: 17 · 2019: 2
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- Merck
- National Institute for Health and Care Research
- Imperial College London
- Public Health England
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- drug addiction, drug withdrawal, antidepressants, opioid analgesics, gabapentinoids, benzodiazepines, Z-drugs, prescription prevalence, socioeconomic deprivation, antidepressant withdrawal symptoms, benzodiazepine withdrawal, patient experience, England, clinical commissioning groups
- MeSH terms
- Pregabalin, Gabapentin, Zolpidem, Acetamides, Adolescent, Adult, Aged, Analgesics, Analgesics, Opioid, Antidepressive Agents, Benzodiazepines, England, Female, Humans, Hypnotics and Sedatives, Male, Middle Aged, Piperazines, Public Health, Pyrimidines, Substance Withdrawal Syndrome, Databases, Factual, Substance-Related Disorders, Azabicyclo Compounds, Young Adult
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