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Abstract
We report about a man in his mid-50s who was prescribed pregabalin (150 mg/day) for neuropathic pain due to a herniated intervertebral disc. Four weeks later, he presented to the emergency room with symptoms consistent with delirium. After ruling out acute intoxication with a substance and neurological causes, collateral information from the family and review of his medical chart indicated potential discontinuation syndrome owing to pregabalin. Following the successful treatment and resolution of delirium, the patient revealed he had been consistently consuming pregabalin doses upwards of 2 g/day over the past 2 weeks, leading to the premature exhaustion of his prescription and an abrupt cessation. The case findings underscore the necessity for physicians to recognise the potential for pregabalin misuse and the associated withdrawal risks, including delirium.
- Delirium
- Drugs misuse (including addiction)
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Background
Pregabalin, a γ-amino butyric acid (GABA) analogue, is approved in the USA for treating fibromyalgia, various forms of neuropathic pain and partial onset seizures.1 Additionally, it is prescribed off-label for a range of clinical conditions,2 with recent trends indicating a surge in its off-label utilisation.3 4 Review articles and case studies have highlighted the potential for pregabalin abuse, and multiple cases have documented withdrawal symptoms following its sudden cessation.5 6 This case emphasises the importance for clinicians to recognise potential misuse of pregabalin to educate patients while prescribing pregabalin and to be cognisant of severe symptoms that might arise from its abrupt discontinuation.
Case presentation
A man in his 50s presented to the emergency department exhibiting prominent visual hallucinations, profound disorientation and marked agitation that developed over a few hours. His accompanying family provided a recent medical history that included a prolapsed intervertebral disc (L2 and L3) 4 weeks ago, which was managed with a 7-day regimen of oral prednisolone, starting at 16 mg/day, which was systematically tapered to cessation by the end of the first week. Concurrently, he was on a daily dose of 150 mg pregabalin, for which he had a prescription covering a 3-month supply. However, his adherence to these medications was unknown to the family members. Notably, he had no psychiatric history or evidence of substance misuse. The patient’s medical history was relevant for well-controlled hypertension treated with 40 mg telmisartan over the past decade.
During the initial assessment, the patient was uncooperative and combative and seemed to engage in conversation with non-existent entities. A comprehensive mental status examination was impossible; however, lack of attention disorientation with respect to time, place and person; rapid and incoherent speech and visual hallucinations were noted. Most of his vital signs were within the standard range, including an oxygen saturation of 98%; nonetheless, he had a mildly elevated heart rate at 98 beats per minute. ECG results revealed sinus tachycardia. The neurological examination findings were normal, and the comprehensive physical assessment was unremarkable.
Investigations
Routine blood test results, including those of a complete blood count, comprehensive liver and renal function tests, thyroid function tests, serum electrolyte levels and blood glucose levels, were all within normal range. The patient tested negative for the five standard drugs (cocaine, amphetamines, marijuana, phencyclidine and opioids) based on a urine toxicology screen (enzyme immunoassay). Notably, this test did not include gabapentinoids, and more specific drug testing was unavailable locally. Additionally, brain computer tomography scans and electroencephalograms were unremarkable.
Differential diagnosis
On further detailed querying, family members revealed that the patient had experienced increased drowsiness and periodic slurred speech since commencing pregabalin treatment 4 weeks ago. They also mentioned a recent consultation with his primary care physician a few days back, although the specifics were unclear. A chart review revealed that the patient was first prescribed pregabalin (150 mg/day) 4 weeks ago and was provided a 3-month prescription. The patient had presented to the physician 3 days earlier after running out of his pregabalin early. He had requested an early refill, citing lost medications. Given his normal pain assessment score, the physician deemed the continuation unnecessary, and a prescription for ibuprofen was provided instead.
The patient had been taking pregabalin for several weeks without exhibiting similar symptoms, and the medical charts suggested a discontinuation of the medication. Therefore, acute delirium as a neurological side effect of pregabalin, as documented in prior case reports,7 8was considered a less likely possibility. Based on the available information, treatment was initiated based on a preliminary working diagnosis of delirium secondary to pregabalin discontinuation.
Treatment
The patient was managed with 2 mg lorazepam and 0.25 mg haloperidol thrice and once per day, respectively, both tapered off over 5 days. His delirium resolved uneventfully, although he had almost no recollection of events over the past few days.
Outcome and follow-up
On regaining his orientation, the patient disclosed that he had escalated his pregabalin usage to 2 g/day over the past 2 weeks. Depletion of a 3-month prescription led him to seek an early refill unsuccessfully. He reported experiencing insomnia and heightened anxiety after stopping pregabalin in the first 2 days after discontinuation, ultimately culminating in the current emergency.
The patient was hospitalised for 5 days and was discharged without medications with a stable physical and mental status. Subsequent follow-up appointments with the family physician at 2, 4, 12 and 36 weeks post discharge revealed him to be clear headed, alert and well oriented. No recurrence of back pain was reported. The patient was offered counselling with substance use services but declined.
Discussion
Gabapentinoids, a class of drugs that includes gabapentin and pregabalin, are analogues of GABA.9 Their structure is similar to that of GABA; however, they do not attach to GABA receptors or affect GABA production or absorption. Instead, they work by inhibiting voltage-dependent calcium channels with the alpha-2-delta-1 subunit, thus decreasing the release of excitatory neurotransmitters presynaptically.10
The surge in pregabalin prescriptions, especially off-label, has raised concerns about potential misuse.3 4 Gabapentin prescriptions in the United States increased by 64% between 2012 and 2016. By 2017, gabapentin was ranked as the 10th most prescribed drug, with 68 million prescriptions.11 12 Off-label uses span over 30 conditions, including restless legs syndrome, generalised anxiety disorder and alcohol withdrawal.2 Similarly, prescriptions of gabapentin, a related drug, have dramatically increased. Since 2006, both drugs have been linked to numerous deaths in the UK, particularly among patients without valid prescriptions.13
Abrupt discontinuation of pregabalin causes various withdrawal signs and symptoms, including diaphoresis, tachycardia, tremors, paranoia, seizures and delirium. The mechanism of discontinuation syndrome is unclear; nevertheless, prevailing theories equate this response to that of withdrawal from substances such as benzodiazepines and ethanol.14 15
Published case reports of pregabalin discontinuation-induced delirium are sparse. Çalışkan et al reported the development of delirium in a woman in her late 60s after discontinuing therapeutic doses of pregabalin.16 Kulig et al reported postoperative delirium due to discontinuing pregabalin.17 Delirium after discontinuing gabapentin, a related compound, was reported by Fabio et al who described an older woman experiencing acute delirium on abrupt gabapentin cessation.18
This case study contributes to the growing yet sparse evidence underscoring the risks of delirium on abrupt cessation of prescribed or recreational pregabalin, regardless of the presence of risk factors, such as advanced age, history of substance use or underlying psychiatric illnesses.
The report further highlights the diagnostic challenges in emergency rooms due to the existing limitations of drug-testing tools. Newer drug-testing tools cover a broader range of substances but often exclude gabapentinoids.19 Comprehensive testing for various substances, including gabapentin, can be achieved using gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry.20 However, these technologies remain out of reach in many settings owing to resource limitations. The growing prevalence of recreational opioid use in various communities, along with the increasing coabuse of opioids and gabapentinoids21 and concomitant overdose risks,22 emphasises the importance of broadening access to elective GC/MS testing in emergency settings.
Patient’s perspective
After I hurt my back, they gave me this drug called pregabalin. It made me feel really relaxed, and soon, I was taking about 15 of those 150 mg capsules every day. It is quite surprising, especially since I've always stayed away from drugs and alcohol. As I was running out, I thought about telling a small lie to my doctor to get more. But he changed my prescription to ibuprofen because my back was getting better. Just thinking about lying made me feel guilty, and I decided to never take something like this again. I felt very nervous in the next few days, and after that, I remember waking up in the hospital to learn what happened. Seeing how worried my family was made me realise my mistake. If I knew that this medicine can make me so addicted, I would have never taken it. I also did not know that stopping a medicine suddenly can make me unwell.
Now, I am focused on following the doctor’s advice. And the good news is, my back feels a lot better.
Learning points
Recognition of abuse: Given the surge in off-label prescriptions of pregabalin and related drugs, such as gabapentin, physicians should be attuned to potential misuse. Observing patterns of rapid medication depletion, requests for early refills and vague descriptions of symptoms can be warning signs.
Delirium on cessation: Abrupt discontinuation of drugs such as pregabalin can have profound neuropsychiatric implications, including delirium, even in patients without apparent risk factors such as advanced age or a history of substance use.
Tailored patient education: Educating patients about the potential for dependence and the hazards of sudden cessation is essential to mitigate the risks.
Continuous monitoring: A proactive follow-up of patients receiving pregabalin is warranted. Such oversight ensures the early detection of potential misuse and timely intervention, significantly reducing the risk of severe outcomes such as delirium.
Access to specific drug testing: Given the evolving landscape of recreational drug use, reevaluation of access to advanced targeted drug-testing tools in emergency rooms is essential for enhancing patient outcomes.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: HA, AV. The following authors gave final approval of the manuscript: HA, AV.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.