# A case series examining the efficacy of gabapentin as a substitution therapy for the treatment of pregabalin use disorder

Benjamin Rolland, Olivier Lejeune, Mathieu Chappuy, Francois Bailly

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Benjamin Rolland, Olivier Lejeune, Mathieu Chappuy, Francois Bailly. A case series examining the efficacy of gabapentin as a substitution therapy for the treatment of pregabalin use disorder. American Journal of Drug and Alcohol Abuse, 2025, 10.1080/00952990.2025.2467458. hal-04968692

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TITLE

A case series examining the efficacy of gabapentin as a
substitution therapy for the treatment of pregabalin use disorder.

AUTHORS

Olivier Lejeune<sup>a</sup>, Mathieu Chappuy<sup>a,b,c</sup>, François Bailly<sup>a</sup>, Benjamin Rolland<sup>b,d,e</sup>

AFFILIATIONS

a. Service d'Hépatologie et d'Addictologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France

b. Service Universitaire d'Addictologie de Lyon (SUAL), Hospices Civils de Lyon, Lyon, France

c. Service Pharmaceutique, Hospices Civils de Lyon, Lyon, France

d. Service Universitaire d'Addictologie de Lyon (SUAL), Pôle MOPHA, CH le Vinatier, Bron, France

e. PSYR2, CRNL, Univ. Claude Bernard Lyon 1, INSERM U1028, CNRS UMR5292, Bron, France

CONTACT

Email : benjrolland@gmail.com

Postal Mail : Prof. Benjamin Rolland, SUAL, Pôle MOPHA, 95 Bd Pinel, 69500 Bron, France

WORD COUNT

2040 words

DISCLOSURE STATEMENT

The authors report no conflicts of interest

FUNDING

This study was not funded
**Abstract**

**Background:** Gabapentinoids are ligands of a brain calcium channel, which are approved for different indications, including epilepsy, neuropathic pain, or generalized anxiety disorder. Among gabapentinoids, pregabalin has been increasingly associated with a risk of pregabalin use disorder (PUD). To date, there is no recommended medical treatment for PUD. However, gabapentin, which has a lower abuse potential, could be used as a substitution therapy to reduce pregabalin withdrawal and craving.

**Objectives:** To report on the experimental use of high-dose gabapentin among those with PUD.

**Methods:** case series of four patients (3 males and 1 female) with severe PUD (average daily doses ranging from 1,200 to 8,400 mg pregabalin), in whom high dose gabapentin was prescribed as a substitution treatment.

**Results:** Upon gabapentin being administered as substitution therapy for pregabalin, all four patients experienced intense craving and distress. Despite receiving high doses of gabapentin, due to the observed levels of craving and distress, all four patients had to be rapidly switched back to pregabalin.

**Conclusions:** Preliminary clinical findings suggest gabapentin is unlikely to be a suitable, lower-risk alternative treatment for people with PUD. Additional examination of candidate medications, including other gabapentinoids, could be useful to identify an effective treatment for PUD.

**Keywords**

Gabapentinoids ; Pregabalin; Gabapentin ; Addiction ; Case Series
Introduction

Gabapentinoid drugs are ligands of the α2δ subunit site of voltage-dependent calcium channels (1). The three gabapentinoids used in medical practice are gabapentin, pregabalin, and mirogabalin (which is not approved in the USA), which are approved for epilepsy, neuropathic pain, or generalized anxiety disorder, respectively (2). More than its sister drugs, pregabalin has been associated with increasing international signals for misuse; addiction, also named pregabalin use disorder (PUD); and potential risks of lethal overdose (3). This increasing public health concern is particularly prevalent in France (4), especially in vulnerable populations such as young and isolated migrants (5), with increasing pregabalin-related overdose-related deaths since 2018 (6).

PUD constitutes a new addiction challenge, exposing patients to a risk of specific withdrawal symptoms, such as irritability, anxiety, sleep disorders, gastrointestinal symptoms, and a risk of complications such as hallucinations, psychosis, or seizures (7,8). It is unclear which medications should be used to prevent or treat pregabalin withdrawal. For example, no strong evidence supports the use of benzodiazepines, as gabapentinoids have no demonstrated GABAergic action (1), while case reports have found inconsistent effectiveness of benzodiazepines for treating pregabalin withdrawal (7, 9). In addition, PUD can be associated with intense craving (7,10), treatment of which is unknown.

In this context, outpatient addiction treatment of PUD can involve slow and supervised pregabalin titration (8,11). However, this strategy is not without potential harms - patients may mix prescription and non-prescribed pregabalin, and thus be exposed to an increased risk of overdose. By analogy with opioid use disorder, another strategy, relying on "substitution", could consist in replacing pregabalin by another drug of the same pharmacological family, but with less risk of loss of control and craving. For example, in opioid use disorder, molecules with a high risk of misuse, such as heroin or morphine, are replaced by other opioid molecules with a lower risk of misuse, such as methadone or buprenorphine, which allows to successfully reduce withdrawal symptoms and craving, to improve quality of life, and to support recovery (12).

Gabapentin appears as a logical candidate for a pregabalin substitution strategy in patients with PUD. Compared with pregabalin, gabapentin has distinct pharmacological features that have suggested that gabapentin could have a reduced potential for abuse (13,14). In particular, gabapentin absorption is slower than that of pregabalin (15). More importantly, by contrast with pregabalin, whose relationship between dose and absorption is linear,
gabapentin absorption is not linear and tends to diminish when the dose increases, reaching a plateau beyond 3,600 – 4,800 mg per day (15). Despite this, gabapentin has also been associated with a risk of abuse (16), even if this risk might be reduced, relative to that of pregabalin (14).

Previous studies of pregabalin for pain have demonstrated that direct substitution of pregabalin for gabapentin is well tolerated (17). Theoretically, clinicians could replace 1 mg pregabalin with 6 mg gabapentin (18). Given that gabapentin is approved in many countries, and because alternative strategies are not well-studied, testing gabapentin as a substitution treatment appeared medically relevant and ethically justified. However, evaluating preliminary clinical experience with case reports is an important step before conducting more thorough clinical studies. Here, we report the findings from a preliminary case series of patients who received gabapentin as a substitution for pregabalin in PUD.

## Methods and Material

This is a retrospective chart review of all patients across three departments who were treated with a switch from pregabalin to gabapentin. We offered this option to the patients, after evaluating with them the pros and cons of this strategy. We selected cases in which the switch from pregabalin to gabapentin was immediate and complete (i.e., pregabalin should have been stopped immediately and not progressively). The switch was performed either at the hospital, or during the outpatient follow-up. Data extracted were deidentified. They included the age and sex of the patient, the main features of his/her medical history, the conditions in which pregabalin was switched for gabapentin, including the dose of pregabalin and the dose trajectory used with gabapentin, as well as the clinical outcome, including the occurrence or modification of withdrawal and craving.

We contacted patients retrospectively (i.e., after gabapentin was introduced), and they provided a signed consent form for anonymous data collection and research use. This study was approved by the institutional review board of the Vinatier Hospital (Avis CEREVI #2024-12). The case series is hereby reported based on the CARE Guidelines (19). The CARE Checklist are displayed in **Supplemental Material**.

## Results

### Case 1
Thirty-three-year-old male with no significant past medical history suffered a fracture of the twelfth thoracic vertebra two years previously. He was started on pregabalin for pain and subsequently required dose escalation, reaching 8,400 mg per day at which time he was referred to an addiction medicine department. At that time, he met seven DSM-5 criteria for PUD, after excluding tolerance and withdrawal. An inpatient pregabalin detoxification was planned, and the decision of substituting pregabalin with gabapentin was taken conjointly with the patient, prior to hospitalization. As soon as the patient was admitted at the hospital, pregabalin was directly replaced for gabapentin, at the immediate dose of 3,600 mg per day. Even if it has been suggested to replace 1 mg pregabalin by 6 mg gabapentin (18), here, however, this dose was chosen because it was the maximum approved dose for gabapentin, and because of the saturation of the absorption of gabapentin above 3,600 – 4,800 mg per day (17), which would have made it absurd to follow the suggested equivalence dose. During the following days, though the patient reported no obvious pregabalin withdrawal symptoms, an intense craving was experienced (self-rated at 8 on a 0-10 numerical scale), associated with severe anxiety.

Case 2

Thirty-five-year-old male with schizophrenia stable on paliperidone (150 mg every month) for two years. Patient had a past history of tramadol use to which he developed a use disorder, but interrupted use one year before presentation. He was initiated by friends with street pregabalin approximately two years before and had developed criteria for severe PUD (9 DSM-5 criteria out of 11) for the year preceding his first consultation in addiction medicine, that is, soon after stopping tramadol. At that time, the dose of pregabalin gradually reached 1,200 mg per day. He first tried to stop pregabalin with no medical supervision, but he experienced confusion and hallucinations which he self-treated with zuclopenthixol. These attempts to stop pregabalin by his own means led to a cessation period that did not exceed several days. An inpatient pregabalin detoxification was planned, and the decision of substituting pregabalin with gabapentin was taken conjointly with the patient, prior to hospitalization. As soon as the patient was admitted at the hospital, 600 mg pregabalin was directly replaced with gabapentin, at the immediate dose of 3,000 mg per day. An add-on diazepam treatment was initiated, at the immediate dose of 30 mg per day. Immediately however, the craving for pregabalin was so strong, i.e., rated at ten on a 0-10 numerical scale, that gabapentin was replaced back with pregabalin at day 3, at the initial dose of 600 mg per day. In the following days, pregabalin dosage was subsequently increased at 900 mg per day. Craving quickly decreased, allowing to subsequently stop diazepam. As the initial
project of inpatient pregabalin detoxification was no longer relevant, the follow-up of the patient was subsequently redefined as a slow outpatient titration of pregabalin dose.

### Case 3

Twenty-four-year-old male patient with no previous history of psychiatric or non-psychiatric disorders, including no other previous SUD. Six-month before his first consultation in addiction medicine, he was initiated on street-purchased pregabalin by a member of his family, and he rapidly developed criteria for severe PUD, and reported the daily pregabalin intake of between 1,200 and 2,000 mg per day. In particular, he experienced substantial family and occupational consequences, as well as intense craving and withdrawal symptoms. After a situation of pregabalin intoxication, he was hospitalized in a psychiatric crisis unit, and then referred into a specialized addiction consultation service. An outpatient replacement of pregabalin by gabapentin was decided conjointly with the patient and his family. Gabapentin was introduced at the dose of 900 mg per day but reached 3,200 mg per day after one week. On gabapentin, the patient did not report specific withdrawal symptoms, but craving was rapidly overwhelming and after ten days, he purchased street pregabalin again. In this context, gabapentin was stopped and switched back to pregabalin, at the dose of 1,500 mg per day. A treatment strategy was subsequently decided with the patient and his family, which consisted in a slow dose titration of prescribed pregabalin.

### Case 4

Forty-one-year-old female patient with a eight-year-long previous history of fibromyalgia, an approximately fifteen-year-long history of dysthymia, and no history of SUD. Pregabalin was introduced seven years earlier in the context of fibromyalgia, and first criteria for PUD occurred after approximately four years of treatment, at the dose of 900 mg per day. For several years, daily intakes oscillated between 900 and 1600 mg per day, in particular in the case of anxiety peaks, leading to regular prescription overlaps. The first consultation in addiction medicine occurred after a change in pregabalin prescriber, during the seventh year of treatment, when the dose was at 1200 mg per day. At that time, the patient met 4 criteria out of 9 (because of situation of prescription drug use disorder), corresponding to a severe PUD. An inpatient detoxification program was proposed, with a switch from pregabalin for benzodiazepines, but this resulted in a premature discharge from the hospital, and immediate resumption of pregabalin at the same dose. Another addiction department was solicited, which proposed an inpatient switch for gabapentin at the initial dose of 2,400 mg
per day, with an increase at 2,800 mg per day on day 3 of hospitalization, and 3,000 mg per day on day 6 of hospitalization. Craving remained intense (not rated), and the patient asked for discharge on day 8. Pregabalin prescription was resumed immediately, and the therapeutic projects changed for a progressive supervised titration of the treatment, based on the mixed use of capsule and syrup forms.

## Discussion

This case series reports the experience of four treated with high dose gabapentin as a potential substitution treatment for PUD. All four patients experienced intolerable cravings and required rapid switch back to pregabalin.

Several hypotheses can explain why gabapentin could not alleviate pregabalin craving. First, it is possibly related to the short half-life of gabapentin (approximately 6 hours for both pregabalin and gabapentin (15)). By contrast, opioid substitution treatments, that is, buprenorphine and methadone, have long half-life (12). Similarly, diazepam, which is recommended for replacing benzodiazepines that have induced benzodiazepine use disorder, has also a long half-life (20). Limited absorption is another possible explanation. The fact that gabapentin absorption can be saturated beyond 4,800 mg per day could explain why gabapentin is ineffective for treating pregabalin craving in patients with PUD, in particular those using very high doses of pregabalin. Moreover, given this specific feature of gabapentin, it appears unwarranted to clinically assess doses up to 3,600-4,800 mg per day. Last, it is possible that gabapentin pregabalin receptor binding differs from gabapentin such that gabapentin is not an effective treatment. Earlier studies suggest that cortical excitability may differ between pregabalin and gabapentin (21). Drug-induced cortical excitability has been linked to a specific risk of SUDs (22), and this difference may explain why gabapentin did not diminish pregabalin craving in the patients treated.

## Limitations

The study was a case series. There was no standard protocol with defined inclusion or exclusion criteria and withdrawal symptoms and craving were not recorded using an established scale, which do not exist for gabapentinoids. The choices of doses and procedures used on each patient followed from a concerted decision by the medical team and the patient and did not follow a specific protocol. The assessment was performed on four patients only, which may be insufficient to conclude that no patient with PUD can benefit from gabapentin substitution. The open label nature of this study could thus have impacted the
evaluation of the outcomes and only randomized controlled trial could allow to properly
assess the potential of high-dose gabapentin in PUD.

Conclusions

Despite the above limitations, all the four patients in whom high-dose gabapentin was
proposed as a substitution therapy for PUD, quickly reported intense craving and distress,
which required to rapidly switch back to pregabalin. The findings of this case series do not
support the further use of gabapentin for PUD.

Acknowledgements

The authors tank Prof. Honora Englander (Portland) for her careful read and precious
comments.
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