Gabapentin withdrawal syndrome in the presence of a taper

Design

Case report

Objective

To report on a geriatric patient who was tapered off gabapentin and transitioned to oxcarbazepine

Methods

The taper occurred over a 5-day period with a decrease of 200 mg daily of gabapentin.  When gabapentin was discontinued, oxcarbazepine was added at 150 mg at bedtime and later increased to 150 mg twice daily 4 days later.

Case Presentation

The patient is an 81-year-old white female with a lifelong history of schizoaffective disorder with bipolar type I tendencies.  Gabapentin was dosed at 400 mg twice daily for 5 years.  The patient's medication regimen includes the following: lithium, carbidopa/levodopa, aripiprazole, lorazepam, and gabapentin. The overseeing team decided to taper gabapentin over a 5-day period with a decrease of 100 mg BID per day of gabapentin. On the fifth day, gabapentin was discontinued and oxcarbazepine 150 mg PO qHS was added, which was increased to 150 mg PO BID four days later.

The first day after gabapentin discontinuation, the patient complained of moderate flu-like symptoms without fever. The patient complained of sore throat, body aches, and cough for five days, and then the patient had a blood pressure spike from a baseline of 110/80 sitting and 106/76 standing to 142/92 and 130/86, respectively, with continued somatic pain. After 9 days of discontinuation, the patient was drooling, slurring speech, disoriented to person, place, and time, sleeping poorly, and experiencing general weakness which caused decreased ambulation.

On the tenth day, the patient’s sitting blood pressure was 170/100 and she complained of chest pain. The patient was subjected to a full-body physical exam after the tapering and there were no abnormalities detected.  The patient was reinstated on gabapentin after labs were screened for abnormalities. The patient’s blood pressure normalized to baseline after the third day of gabapentin reinstatement.

Study Author Conclusions

Gabapentin discontinuation should follow a course similar to benzodiazepines: a slow taper that sustains over a period of weeks to months.

The gabapentin taper in this patient occurred over a 5-day period with a decrease of 100 mg BID per day of gabapentin. Although this patient had withdrawal symptoms after an extended gabapentin taper, this is an uncommon phenomenon and discontinuation of gabapentin results in few side effects for the vast majority of patients. However, the clinician should be vigilant for the possibility of a severe withdrawal syndrome even after a gradual taper and treat accordingly.

The authors propose that a gabapentin taper should follow a course similar to that of a benzodiazepine taper: slowly and over a period of weeks to months.

Gabapentin Withdrawal: Case Report in An Older Adult and Review of the Literature

Case report

A 75-year-old woman was admitted to the hospital due to recurrent falls. Her past medical history was significant for fibromyalgia and postherpetic neuralgia. Patient was taking gabapentin 1,800 mg/day for neuralgia, and sertraline 300 mg/day and lorazepam 3 mg/day for depression. It was suspected that her falls were a side effect of psychotropic drugs. Gabapentin was tapered and discontinued over 10 days. Lorazepam was tapered by 1 mg/day over one week, starting one day after the start of gabapentin taper. After tolerating a 10-day taper well, the patient complained of mild abdominal pain and headache on day 11. Blood pressure was 190/95 mmHg.

The next day, the patient reported chills, cold sweats, nausea, and insomnia, as well as increased agitation and the development of anorexia. Suspecting benzodiazepine withdrawal, she was reinitiated on lorazepam and also attempted a longer-acting benzodiazepine; however, the symptoms failed to improve over the following five days. X-rays, imaging, and labs were normal except for hypokalemia (2.6 mEq/L) and mildly elevated liver enzymes. Potassium replacement was initiated. The patient continued suffering from abdominal pain "worse than childbirth" as well as agitation, chills, and diaphoresis. Suspecting gabapentin withdrawal, gabapentin 400 mg was given immediately and restarted at 600 mg at bedtime. Blood pressure was normalized and diaphoresis was ceased, but the patient only experienced partial relief of anxiety and abdominal pain and continued to report insomnia. Gabapentin was then increased to 1,400 mg/day, and the patient's withdrawal symptoms were resolved completely in three consecutive days. 

The mechanism of action of gabapentin, particularly in older adults, is poorly understood. A conservative approach to the off-label use of gabapentin with clearly defined endpoints for dosage titration and discontinuation is suggested. In older adults and in the presence of psychiatric illness, gabapentin discontinuation should follow a slow tapering schedule, as for benzodiazepines (e.g., biweekly reduction of 10–25% of dose), and patients should be monitored carefully for emerging withdrawal symptoms.

Retrospective Analysis of Gabapentin for Alcohol Withdrawal in the Hospital Setting: The Mayo Clinic Experience

Design

Retrospective cohort study 

N= 443

Objective

Study Groups

Gabapentin (n= 128)

Lorazepam (n= 253)

Both (n= 62)

Inclusion Criteria

Hospitalized patients aged ≥ 18 years with a primary indication of alcohol withdrawal

Exclusion Criteria

Initial admission to the ICU, discharge within 24 hours, primary seizure disorder, known gabapentin allergy or intolerance, concurrent intoxication or overdose involving substances other than alcohol or cannabis, and preadmission gabapentin use greater than 900 mg daily, on treatment with adjuvant medications (such as antipsychotics or anticonvulsants) other than divalproex, clonidine, thiothixene, or haloperidol

Methods

Based on retrospective medical chart review, patients were categorized into three groups, the benzodiazepine group received a standard CIWA-triggered benzodiazepine protocol, the gabapentin group received ≥ 2 doses of gabapentin (totaling > 900 mg total daily dose for at least 1 day) without benzodiazepine, and the combination group started concurrently on fixed-dose gabapentin taper and CIWA-triggered benzodiazepines. 

Specifically, for patients with estimated glomerular filtration rates (eGFR) > 60 mL/min, gabapentin was given 900 mg 3 times daily for 4 days, 600 mg 3 times daily for 3 days, 300 mg 3 times daily for 2 days, and then discontinuation; for patients with eGFR of 30 to 60 mL/min, dosing was 600 mg 3 times daily for 4 days, 300 mg 3 times daily for 3 days, 100 mg 3 times daily for 2 days, and then discontinuation. Other adjuvant medications include divalproex sodium taper, clonidine, and thiothixene or haloperidol at physicians' discretion. 

Duration

Hospital admission: January 1, 2016, to April 30, 2018

Outcome Measures

Primary outcome: length of stay, defined as the time from admission to either discharge or 36 hours with Clinical Institute Withdrawal Assessment (CIWA) score < 10

Baseline Characteristics

Gabapentin (n= 128)

Lorazepam (n= 253)

Mean age, years 

Female

White

Mean admission CIWA score 

No. of prior admits for alcohol withdrawal
in last 12 mo

History of alcohol withdrawal seizures and delirium tremens, no.

Prior treatment with gabapentin for alcohol withdrawal 

Results

Endpoint

Gabapentin (n= 128)

Lorazepam (n= 253)

p-value

Transferred to ICU for any reason, no.

Seizure during hospitalization, no.

Delirium tremens during hospitalization, no. 

Length of stay, hours 

Mean 

Max CIWA score 

Combination (n= 62)

Median total gabapentin, mg (Quatile 1, Q3)

Median total benzodiazepines, mg (Q1, Q3)

Most patients (n= 374; 84.4%) did not receive other adjuvant medications.

Study outcomes did not significantly change with covariant adjustments. 

Adverse Events

N/A

Study Author Conclusions

A fixed-dose gabapentin taper protocol appears to be an effective and safe alternative to CIWA-driven benzodiazepines in patients hospitalized with alcohol withdrawal syndrome, though further research is necessary to define the potential subpopulations that benefit most.

InpharmD Researcher Critique

Given the retrospective nature of the study, certain factors that might affect the therapeutic choice of either gabapentin or benzodiazepine in the first place couldn't be fully captured and analyzed. Additionally, the study was not powered to detect the differences in the incidence of seizure or delirium tremens. 

Patents' baseline characteristics need to be carefully evaluated, such as current dosing, duration of therapy, renal function, and age, before utilizing this specific gabapentin tapering regimen in other scenarios. 

Efficacy and Tolerance of Long-Term, High-Dose Gabapentin: Additional Observations

Design

Open-label phase following a blinded, placebo-controlled, add-on dose efficacy study

N= 23

Objective

To report findings from the US Gabapentin Study Group that have practical implications for patient management

Study Groups

Open-label treatment (N= 23)

Inclusion Criteria

Received at least one and not more than two antiepileptic drugs (AEDs) at a stable dosage for 3 months prior to screening with an average of ≥ 4 medically refractory partial seizures in each 4 week period of the 3 months prior to screening

Exclusion Criteria

Not explicitly stated

Methods

Following a double-blind study period in which patients received placebo or gabapentin 600, 1,200, or 1,800 mg daily in addition to concurrent AED regimen for 12 weeks, each patient was titrated to gabapentin 1,200 mg daily in 2 weeks and continued gabapentin in the open-label study period. Gabapentin was administered three times daily in equal doses in this phase of the study.

Patient doses were titrated up by 200 to 300 mg/day every 2 to 4 weeks. If intolerable adverse events occurred, patients were dose reduced. Patients were following as long as possible once on maximally tolerated gabapentin dose. If the response was deemed unsatisfactory by the clinician, gabapentin was discontinued by reducing gabapentin at a rate of 200 to 300 mg/day every 3 to 7 days.

Outcome Measures

Seizure frequency

Baseline Characteristics

Open-label treatment (N= 23)

Age, years (range)

Female

Median duration of epilepsy, years (range)

Median number of seizures per 4 weeks (range)

Number of concurrent AEDs

1

2

12 (52.2%)

11 (47.8%)

Results

Gabapentin was discontinued at a rate of 200 mg/week in one patient, 300 mg/week in 3 patients, and 300 mg/3 days in 3 patients based on data from 7 patients who discontinued gabapentin treatment. Patients who were tapered at a rate of 200 to 300 mg/3 to 7 days did not experience an increase in seizure frequency during tapering or after completion of the taper compared to baseline.

Adverse Events

Adverse events were not reported for patients who required tapering of gabapentin.

Study Author Conclusions

Our results extend previous observations by indicating that GBP retains efficacy for 4 years of treatment, with good tolerance of 2,400 mg/day in most patients. A mild pharmacodynamic interaction with concurrent AEDs is suggested by our observations; this can be easily managed by reducing concurrent AED dosage. The upper dosage limit for GBP efficacy and tolerability remains to be determined.

InpharmD Researcher Critique

This study had a small sample size and used various tapering regimens, which limits conclusions regarding a safe tapering regimen. It appears tapering at a rate of 200 to 300 mg every 3 to 7 days may not increase seizure frequency. Additionally, this study included a relatively young population, so results may not be generalizable to elderly patients.