Introduction
There is an increasing incidence of gabapentinoid (pregabalin and gabapentin) prescribing worldwide, with increased volume of prescribing of these drugs reported in the US, UK, Scotland and Ireland [ 1–4 ]. Alongside the increased volume of gabapentinoid prescribing is co-prescribing with other psychotropic and pain medication such as opiates, benzodiazepine and z-class drugs [ 5 ] Evidence is accumulating that gabapentinoid prescribing alone and when co-prescribed are independently associated with increases in drug-related deaths, with risk of death increasing with stronger doses of opiates and/or gabapentinoids [ 6–8 ].
This emerging evidence has prompted national regulatory bodies to take action in terms of issuing risk warnings to the public and to prescribing physicians. For instance, the Federal Drug Agency (FDA) has warned of serious breathing difficulties with gabapentin and pregabalin use in patients with existing respiratory risk conditions and/or respiratory risk factors. Respiratory risks include: use of central nervous system (CNS) depressants or opioids; chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD) as well as demographic risk factors, particularly older age [ 9 ]. The evidence brought forth by the FDA was based on forty nine case reports between 2012 to 2017 where significant adverse events occurred, including drug-related death [ 9 ].
Whilst the risk of gabapentinoids are becoming clearer, the underlying reasons behind the initial initiation of the drug is frequently less clear. Patient, physician and health system factors all play a role in the increase in prescribing of gabapentinoids [ 1 , 10 ]. The public health crisis of opiate prescribing, particularly in the US, has brought into focus that effective strategies require a multifactorial understanding at the patient, physician and health system levels. Though general practitioners prescribe the greatest volume of opiates, there is evidence that hospital initiation of opiates in opiate-naïve patients at discharge is increasing and may be an important driver of longer-term opiate use [ 11 ]. Whether the same issue arises in the case of gabapentinoid prescribing is not yet known.
This case series was prompted by a critical incident in a single general practice. Critical incident reporting is an effective way to address patient safety in a general practice and enable a culture of quality improvement [ 12 ]. A female patient in her 60’s taking long-term gabapentin was found dead at home. She was well known to the general practitioners who had been prescribing painkillers for a variety of pain-related complaints. It was acknowledged by the medical team and discussed with the patient that the combination of Gabapentin, Tapentadol and Zoplicone significantly increased her risk for drug related toxicity. It had proved very difficult to modify this patient’s drug regimen, particularly as initiation of these drugs has taken place in a hospital-based pain clinic.
The primary aim of this case series, prompted by a critical incident of a drug-related death, is to investigate how patient, physician and health-system factors influence gabapentinoid prescribing in primary care, and to assess their contribution to unexplained deaths. The objectives were to: quantify gabapentinoid prescribing over a 11-year period; examine the cause of death in patients taking gabapentinoid drugs at the time of their death for both expected and unexpected deaths using post mortem and toxicology reports when unanticipated deaths occurred. Lastly, this study in a single general practice served as a feasibility study to a case control study that would examine modifiable and non-modifiable factors that might reduce the likelihood of gabapentinoid associated deaths in a larger, more representative sample of general practices.
Methods
In this case series, we examined gabapentinoid prescribing in a single general practice over a 11-year period. We extracted the following variables from each patient’s clinical record(1) patient characteristics: age, gender, co-morbidity, co-prescription of drugs implicated in drug-related death (benzodiazepine, z-class, opiate and alcohol), and the clinical indication for initiation of gabapentinoid prescription; (2) physician related prescribing issues- the clinical setting of medication initiation (general practice or hospital clinic) and specialty of the prescribing physician; and (3) health system factors in terms of monitoring or changes in prescriptions.
For patients who had died, we classified the deaths as expected where a known terminal condition had been diagnosed and palliative care initiated. Unexpected death occurred when a patient died suddenly and their death had not been expected by their general practitioner or other attending health professionals. For unexpected deaths we wrote to the Coroner requesting post mortem details and toxicology results (blood and urine).
Prompted by an unexpected death, this critical incident study was carried out in a practice where one of the authors (TF) is a general practitioner for the past 18 years. AG collected and prepared the practice data as part of a research summer student placement based in the Department of General Practice, RCSI University of Medicine and Health Sciences in 2023.
Results
Descriptive statistics of gabapentinoid prescribing
The time trends of prescribing according to type of gabapentinoid drug is summarised in Figure 1 . Prescribing peaked in 2019 and reduced slightly in the following years. Similar to national data, females accounted for approximately three quarters of individuals prescribed gabapentinoids and pregabalin was prescribed in two thirds of individuals during the 2012–22 time period.
Gabapentinoid deaths- unexpected and expected
There were 36 deaths (four unexpected and 32 expected) during the study period. Table 1 provides details of patients who died and were concurrently prescribed a gabapentinoid at the time of their death. The majority of patients were over the age of 70 ( n = 29, 81%) and female ( n = 19, 53%). Patients also had significantly high multimorbidity (median Charlston Index score 7, range 1 to11) and polypharmacy (median number of drugs 11, range 2 to 21) scores.
Table 1.
Patient characteristics- expected* and unexpected deaths.
| ID | Age | Sex | Charlston Comorbidity index | Number of medicines co-prescribed | Gabapentinoid Prescribed | Clinical Indication for Gabapentinoid | Specialty Hospital Initiated | Off Label | Opiate | Benzodiazepine | Alcohol misuse | Principal cause of death |
| 1* | 60–69 | F | 11 | 21 | Gabapentin 100 mg daily | Low back pain | Pain Yes | No | Tapentadol 100 mg BD | Zopiclone 7.5 mg | Yes | Mixed drug and alcohol toxicity |
| 2* | 50–59 | F | 10 | 10 | Pregabalin 100 mg QDS | Sciatica | Pain Yes | No | Oxycontin 10 mg Oxynorm 5 mg | Alprazolam 1 mg | No | Rupture Aneurysm |
| 3* | 80–89 | F | 11 | 10 | Pregabalin 150 mg daily | Dermato myositis | Rheumatology Yes | Yes | No | No | No | Cardiac arrhythmia; IHD |
| 4* | 70–79 | F | 3 | 12 | Gabapentin 600 mg BD | SLE | Rheumatology Yes | Yes | No | Zolpidem 10 mg | No | Cardiac arrhythmia; IHD |
| 5 | 70–79 | F | 9 | 14 | Gabapentin 300 mg BD | Unclear | Unclear | Unclear | No | Zopiclone 10 mg | No | Metastatic Breast Cancer |
| 6 | 70–79 | M | 10 | 2 | Gabapentin 100 mg BD | Unclear | Unclear | Unclear | No | No | No | Old age |
| 7 | 90–99 | M | 6 | 8 | Gabapentin 100 mg TDS | Sciatica | Pain Yes | No | No | Zolpidem 10 mg | No | Metastatic Colorectal Carcinoma |
| 8 | 80–89 | F | 8 | 13 | Gabapentin 300 mg TDS | Tempero-Mandibular Pain | Pain Yes | Yes | No | Zopiclone 7.5 mg | No | COPD |
| 9 | 30–39 | F | 2 | 8 | Gabapentin 100 mg TDS | Neuropathic cancer pain | Oncology Yes | No | Tramadol 100 mg QDS | No | No | Metastatic Cancer |
| 10 | 80–89 | M | 7 | 20 | Gabapentin 100 mg | Unclear | Geriatrics Yes | Unclear | No | No | No | CVA |
| 11 | 80–89 | M | 7 | 11 | Gabapentin 100 mg TDS | Peripheral Neuropathy diabetic | Diabetes Yes | No | No | No | No | IHD |
| 12 | 80–89 | M | 7 | 13 | Gabapentin 100 mg BD | Unclear | Unclear | Unclear | No | No | No | Intersitital Lung Disease |
| 13 | 70–79 | M | 5 | 9 | Gabapentin 100 mg TDS | Unclear | Unclear | Unclear | Tadenafil 100 mg daily | No | No | Lung Cancer |
| 14 | 80–89 | M | 11 | 15 | Gabapentin 100 mg TDS | Unclear | Unclear | Unclear | Oromorph | Zolpidem 10 mg | No | Prostate Cancer |
| 15 | 70–79 | F | 11 | 15 | Gabapentin 100 mg BD | Unclear | Unclear | Unclear | Morphine Sulphate (MST) | No | No | Metastatic Renal Cell Carcinoma |
| 16 | 80–89 | F | 5 | 11 | Pregabalin 75 mg daily | Unclear | Unclear | Unclear | No | Alprazolam 0.25 mg BD | No | Respiratory Failure |
| 17 | 70–79 | F | 6 | 11 | Pregabalin 75 mg | Sciatica | Pain Yes | No | No | No | No | Lung Cancer |
| 18 | 60–69 | M | 4 | 9 | Pregabalin 25 mg Capsules | Ano-Rectal Cancer | Oncology Yes | Yes | Oxycontin | Temazepam 10 mg | No | Lung Cancer |
| 19 | 80–89 | F | 5 | 4 | Pregabalin 75 mg daily | Unclear | Unclear | Unclear | No | No | No | Unclear |
| 20 | 70–79 | M | 7 | 13 | Pregabalin 75 mg BD | Neurogenic Pain | Oncology Yes | No | Fentanyl Hydromorphine | No | No | Renal Cell Carcinoma |
| 21 | 90–99 | F | 7 | 11 | Pregabalin 100 mg | Osteoporosis pain | Rheumatology Yes | Yes | No | No | No | Pancreatic Cancer |
| 22 | 80–89 | F | 7 | 12 | Pregabalin 225 mg | Sciatica | Endocrinology Yes | No | Buprenorphine | No | No | Old age |
| 23 | 30–39 | M | 2 | 14 | Pregabalin 150 mg BD | Unclear | Unclear | Unclear | Morphine Sulphate | No | No | Stage 4 Non Small Cell Lung Cancer |
| 24 | 80–89 | M | 6 | 20 | Pregabalin 125 mg | Unclear | Unclear | Unclear | No | No | No | Old age |
| 25 | 80–89 | F | 4 | 18 | Pregabalin 75 mg | Unclear | Unclear | Unclear | Buprenorphine | No | No | Multiple Myeloma |
| 26 | 70–79 | M | 10 | 13 | Pregabalin 25 mg | Unclear | Unclear | Unclear | Oxycondone | No | No | Metastatic Bladder Cancer |
| 27 | 50–59 | M | 1 | 14 | Pregabalin 225 mg | Neurogenic Pain | Pain Yes | No | No | Chlordiaze poxide | No | Suicide |
| 28 | 80–89 | F | 5 | 12 | Pregabalin 75 mg | Unclear | Unclear | unclear | No | No | No | Old age |
| 29 | 80–89 | M | 8 | 13 | Pregabalin 75 mg | Neurogenic Pain | Diabetes Yes | No | No | No | No | Dementia |
| 30 | 80–89 | F | 5 | 11 | Pregabalin | Unclear | Geriatrics Yes | No | No | No | No | Old age |
| 31 | 60–69 | M | 5 | 8 | Pregabalin 75 mg | Unclear | Unclear | Unclear | No | No | No | Gastric Cancer |
| 32 | 80–89 | F | 7 | 8 | Pregabalin 50 mg | Unclear | Unclear | Unclear | No | No | No | Sepsis |
| 33 | 80–89 | F | 10 | 13 | Pregabalin 75 M mg BD | Unclear | Unclear | Unclear | No | Zopiclone | No | COPD |
| 34 | 30–39 | M | 3 | Pregabalin 25 mg | Metastatic Cancer | Oncology Yes | Yes | Hydromorphone Oxynorm | No | No | Duodenal Cancer | |
| 35 | 80–89 | M | 6 | 13 | Pregabalin 25 mg | Sciatica | Pain Yes | Yes | Buprenorphine | No | No | Pneumonia |
| 36 | 70–79 | M | 5 | 10 | Pregabalin Lyrica 50MG Capsules | Unclear | Unclear | Unclear | Oxycontin Oxynorm | No | No | Lung Cancer |
Hospital initiation of gabapentinoids occurred in 19 (53%) of patients. Off label use was determined in 6 (17%) patients but unclear in a further 16 (44%). Co- prescription of other harmful drugs was common with 15 (42%) taking an opiate, 11 (31%) taking a benzodiazepine; 4 (11%) taking both and 22 (61%) taking either an opiate or benzodiazepine. There was no clinical note entry for harmful alcohol consumption in any of the 36 patients.
Four patients died unexpectedly during the study period. Table 2 provides details of post mortem findings and toxicology results. Patient 1 was found to have their cause of death attributed to drug and alcohol toxicity; this was the patient who prompted the initial critical incident. Two other patients had drug levels in the therapeutic range at the time of their death. Patient 2 had a blood toxicology report that showed benzodiazepine and opiate in the therapeutic range with pregabalin in their urine toxicology. Patient 3 had blood toxicology in the therapeutic range for pregabalin, diphenhydramine and ketamine. Patient 4 had a negative toxicology screen at the time of their death.
Table 2.
Descriptive characteristics, clinical indication, prescribing history and post mortem and toxicology findings.
| Patient 1 |
| Descriptive characteristics- female; aged between 60–69, Charlston co-morbidity index 11; polypharmacy 21 medications; history of alcohol misuse |
| Clinical indication- low back pain |
| Prescribing history- hospital initiated pain clinic; co-prescribed Zopiclone |
| Circumstances- discovered lying in her bathroom; last spoke with neighbour four days previously |
| Toxicology- blood toxic levels of citalopram, zopiclone; therapeutic levels of tapentadol and gabapentin; ethanol present in blood 91mg%, just below toxic levels (>100mg%). Urine screen positive for citalopram, gabapentin, quinine, tapentadol and zopiclone. |
| Cause of death- mixed drug and alcohol toxicity |
| Patient 2 |
| Descriptive characteristics- female; aged between 50–59; Charlston co-morbidity index 10; polypharmacy 10 medications |
| Clinical indication- low back pain |
| Prescribing history- hospital initiated pain clinic; co-prescribed Oxycontin |
| Circumstances- found in bed |
| Toxicology- blood positive for paracetamol, alprazolam, oxycodone, zolpidem, baclofen, fluoxetine all in the therapeutic range. All present in urine with pregabalin identified additionally. Drugs deemed to be non contributory to the patient’s death |
| Cause of death- ruptured berry aneurism of the brain |
| Patient 3 |
| Descriptive characteristics- female; aged between 80–89, Charlston co-morbidity index 11; polypharmacy 10 medications; history of alcohol misuse |
| Clinical indication- dermatomyositis |
| Prescribing history- hospital initiated rheumatology clinic; no prescribing of benzodiazepine |
| Circumstances- fell at home and brought to accident and emergency department where death occurred |
| Toxicology-blood positive for pregabalin, diphenhydramine, ketamine, paracetamol and propranolol all in the therapeutic range. |
| Cause of death- hypoxic ischaemic encephalopathy due to presumed cardiac arrhythmia, secondary to ischaemic heart disease |
| Patient 4 |
| Descriptive characteristics- female; aged between 70 and 79, Charlston co-morbidity index 3; polypharmacy 12 medications |
| Clinical indication- Systemic lupus erythematosus (SLE) |
| Prescribing history- hospital initiated rheumatology clinic; no prescribing of benzodiazepine |
| Circumstances of death- discovered by husband in the morning, in bed; last spoke to husband the previous evening prior to bedtime |
| Toxicology- blood drug screen negative for ethanol, opiates, cocaine, barbiturates, methadone, cannabinoids, amphetamines, phenothiazines and benzodiazepines |
| • Cause of death- cardiac arrhythmia secondary to myocardial fibrosis and ischaemic heart disease |
Discussion
Summary of findings
The epidemiology of prescribing in this single general practice follows a similar pattern as the national prescribing data [ 8 ], with an increase in gabapentinoid prescribing during the study period alongside significant co-prescribing with opiates and benzodiazepines, with 22 (61%) of patients taking either drug with a gabapentinoid. Most of the deaths of patients were expected and planned for in terms of a gabapentinoid drug accompanying an opiate drug use for terminal care pain relief. The majority of patients were elderly with significant multimorbidity, receiving polypharmacy drug regimes. Nearly all gabapentinoid prescriptions were initiated in a hospital setting, with a large proportion of patients receiving a gabapentinoid for an ‘off label’ clinical indication.
Of the four unexpected deaths, only one was directly attributable to drug and alcohol toxicity. This confirms the known risks of alcohol with certain psychoactive medications, including gabapentinoids [ 13 ]. The three other unexpected deaths were due to other causes with toxicology reports showing combinations of drugs, including gabapentinoids, all within a therapeutic range. These findings demonstrate the value of post mortem and toxicology reports in unexpected community-based deaths when determining true cause of death [ 14 ].
The initial critical incident of a drug related death was confirmed at post mortem and toxicology.This case series also shows that many patients take gabapentin in combination with opiates as part of end-of-life care. Only a minority of patients who were prescribed gabapentinoids were at risk of unexpected drug-related death and no other patients were confirmed to have suffered an unexpected drug-related death during this 11-year period. On the one hand, this was a reassuring finding. On the other hand, it highlights the difficulty in combating opiate and/or gabapentinoid-associated death in primary care settings. Each practice will have relatively few ‘at-risk’ patients and any quality improvement initiative such as use of comparative clinical data, audit and feedback and/or use of key opinion prescribing leader will have only limited impact at the individual practice level.
Comparison with existing literature
There is growing evidence concerning the risk of sudden death with gabapentinoid drugs, particularly in relation to co-prescribing with opiates and/or benzodiazepines [ 8 , 15 ]. This recognition has prompted some drug regulatory authorities to re-classify gabapentinoids, for example the Medicines and Healthcare Regulatory Authority (MHRA) reclassified gabapentins as Schedule II medications and Class C drugs in April 2019 [ 15 ]. Our study shows that gabapentinoid related death in this practice was similar in many respects with other community-based deaths, occurring in a patient with known polypharmacy, taking at risk drugs including opiates and benzodiazepines, against a background of ongoing alcohol misuse [ 6–8 ].
A recent large community-based randomised controlled trial in the US that used a multi-faceted approach including different forms of communication alongside community-based Naloxone treatment did not have an impact on reducing the incidence of drug-related deaths in primary care [ 16 ]. More positively, a recent non-randomised study in hospitalised patients taking a gabapentinoid, a direct-to-consumer (patient) educational brochure had a small but significant impact in deprescribing of the gabapentinoid at 8-week follow up [ 17 ].
Strengths and limitations
This case series shows the value of a critical incident approach after a significant patient safety event, in this case when a patient dies unexpectedly from a drug-related prescribing cause [ 12 ].
The limitations of this study are that this is an observational descriptive study limited one single general practice. In order to estimate a practice-based absolute/attributable risk, exposure to all patients from Gabapentinoid drugs during this period would be needed. Some important elements in patient’s clinical records were incomplete or missing: this includes date of initiation and clinical indication for Gabapentinoid; and lastly, blood monitoring data particularly estimated Glomercular Filtration Rate (eGFR) in relation patients with impaired renal function. Our findings require replication in a larger sample of practices, with initial exposure (prescription of gabapentinoid and other drugs) measured at baseline and outcome (drug-related unexpected death) at follow up. More careful characterisation of clinical indication for prescription of gabapentinoid and setting of initiation (type of hospital clinic and more detailed characteristics of prescribing physician) would also be helpful in terms of potential interventions that may mitigate inappropriate use of gabapentinoids in primary care.
Implications for research and clinical practice
Findings from this study require replication in a larger sample of practices. It appears to be a feasible approach when examining patient, practice and health-system factors that relate to safer gabapentinoid prescribing. We plan to undertake a larger case control study of unexpected gabapentinoid deaths in primary care in relation to hospital initiated prescribing. Based on our finding of 22 (61%) being exposed to a gabapentinoid drug and either an opioid or benzodiazepine, and assuming a differential 70% exposure in cases (unexpected gabapentinoid death) and 50% exposure in controls (prescribed gabapentinoid but alive) we will require 61 cases and 244 controls (ratio of 1:4) to test the hypothesis of a difference in hospital initiation of gabapentinoids between the two groups at 80% power and a significance level of 0.05 (STATCALC, EPI INFO). We plan to recruit between 15 and 20 practices to achieve this sample size. These estimates are based on pragmatic considerations of obtaining four controls for every case of gabapentinoid-associated death and the feasibility of this approach is grounded from this study of four to five unexpected deaths in each general practice.
Implications for clinical practice
The clinical implications for a single general practice are that care needs to be taken when co-prescribing gabapentinoid drugs with either opiates or benzodiazepines. Much of the prescribing is outside of a general practitioner’s range of initial clinical responsibility; as we have found that gabapentinoids are often hospital initiated (usually from pain, rheumatology or oncology clinics). The challenge for general practitioners is that they have to continue these gabapentinoid prescriptions, monitor co-prescribing and the presence of risk factors that may affect excretion, particularly impaired renal function. General practitioners continue to have clinical responsibility for these hospital-initiated drugs. As was the case with the patient who died unexpectedly, knowledge about the risks of co-prescribing with opiates and/or benzodiazepines needs to be shared with patients, and clearer prescribing protocols between primary and secondary care for gabapentinoid drugs are needed. Unfortunately, current evidence suggests that shifting patients off drugs such as opiates or benzodiazepines is extremely challenging [ 16 , 18 ]. It is likely that discontinuation of gabapentinoids is also likely to be very difficult in primary care without broader psycho-social support.
Conclusion
Critical incident reporting in terms of prescribing practice is an important element of reflective practice and promotion of a safer prescribing environment in general practice. This study confirms that a large part of gabapentinoid prescribing is hospital initiated [ 19 , 20 ]. General practitioners need to remain vigilant when taking on the responsibility of hospital-initiated drugs, particularly opiates, benzodiazepines, gabapentinoids, particularly when prescribed in combination and for an ‘off-label’ clinical indication.
Acknowledgements
The authors would like to than the offices of the Dublin and Wicklow Coroners for providing post mortem and toxicology reports for the four unexpected deaths outlined in Table 2 . TF conceived the research idea and both authors (AG and TF) were responsible for data collection, analysis and write up of the paper.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethics approval and consent to participate
This study was done as a clinical audit for the Irish College of General Practitioners (ICGP) professional competence scheme 2024/5, consistent with Section 4.1.4 ‘Activities that do not require REC approval’ from HSE National Framework for Governance, Management and Support of Health Research, September 2021; all data were anonymised in the practice setting and all participants described in the paper are deceased. TF is the data controller.
Data availability statement
Data is available from corresponding author who is the data controller.
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