What is the recommended pregabalin dosing regimen for cocaine use disorder, including titration schedule and adjustments for renal impairment?

Pregabalin for Cocaine Use Disorder: No Established Clinical Dosing Regimen

There is no FDA-approved medication for cocaine use disorder, and pregabalin has not been studied in human clinical trials for this indication—only preclinical animal data exist showing potential efficacy. 1, 2

Current Evidence Status

Lack of Human Clinical Data

• No clinical trials have evaluated pregabalin dosing, safety, or efficacy in humans with cocaine use disorder, despite promising preclinical findings in rat models showing reduced cocaine self-administration and relapse prevention at oral doses of 10-30 mg/kg. 2
• The most recent comprehensive review of medications for cocaine use disorder (2019) does not include pregabalin among investigated treatments, indicating absence of human trial data. 1
• Psychostimulants, modafinil, bupropion, topiramate, and disulfiram show the most promise in existing literature, but even these lack strong evidence due to study heterogeneity, small sample sizes, and inconsistent results. 1

Preclinical Findings Only

• In rat models, oral pregabalin at 10 mg/kg and 30 mg/kg reduced cocaine self-administration over 6-hour periods without affecting food self-administration, suggesting specificity for cocaine-seeking behavior rather than general behavioral suppression. 2
• Both doses completely abolished cocaine-seeking behavior triggered by the pharmacological stressor yohimbine and by cocaine-associated environmental cues. 2
• The proposed mechanism involves reducing excitatory neurotransmitter release and post-synaptic excitability, similar to pregabalin's effects in reducing alcohol intake and preventing alcohol relapse. 2

Critical Safety Concerns for Off-Label Use

Renal Function Monitoring is Mandatory

• Pregabalin clearance is directly proportional to creatinine clearance (56% correlation), with area under the curve (AUC) and half-life increasing dramatically as renal function declines. 3
• In patients with creatinine clearance 30-60 mL/min, a 50% dose reduction is required; for each additional 50% decrease in creatinine clearance, daily doses should be reduced by another 50%. 3
• Calculate creatinine clearance using the Cockcroft-Gault equation before initiating any pregabalin therapy, as this is non-negotiable for safe dosing. 4

Neurological Toxicity Risk

• Pregabalin-associated myoclonic encephalopathy can occur even at therapeutic plasma concentrations (3.42 μg/mL) in patients with acute renal failure, suggesting a threshold phenomenon rather than simple drug accumulation. 5
• Common dose-dependent adverse effects include dizziness (23-46%), somnolence (15-25%), peripheral edema (10%), and visual disturbances, which may be particularly problematic in patients with active substance use disorders. 6, 4

Lack of Dosing Guidelines

• No established titration schedule, target dose range, or maximum dose exists for cocaine use disorder, as all existing pregabalin dosing guidelines address neuropathic pain, epilepsy, or generalized anxiety disorder—not addiction treatment. 4
• Standard neuropathic pain dosing (starting 75 mg twice daily, target 300 mg/day, maximum 600 mg/day) cannot be extrapolated to cocaine use disorder without clinical trial data demonstrating safety and efficacy in this population. 4

Alternative Evidence-Based Approaches

Medications with Human Trial Data

• Disulfiram has demonstrated the most consistent effect to reduce cocaine use across multiple controlled trials, making it the closest option to an evidence-based pharmacotherapy. 7
• Baclofen, modafinil, tiagabine, and topiramate have shown efficacy in double-blind, placebo-controlled trials, though confirmatory studies are needed. 7

Psychosocial Interventions Remain First-Line

• Contingency management has the strongest evidence base for treating cocaine use disorder and should be the foundation of treatment. 1
• Medication-assisted treatment should be considered only for patients who do not respond to psychosocial interventions alone, given the significant morbidity of cocaine use disorder and relatively low risks of investigated medications. 1

Clinical Bottom Line

Pregabalin cannot be recommended for cocaine use disorder outside of a research protocol, as no human dosing, safety, or efficacy data exist. 1, 2 If considering off-label use based on preclinical data, mandatory renal function assessment, close neurological monitoring, and informed consent about the complete absence of human trial data are essential. 3, 5 Disulfiram or evidence-based psychosocial interventions (particularly contingency management) represent more appropriate first-line approaches. 1, 7