Should You Prescribe Oral Thiamine for Chronic Alcoholics?

Background: Alcoholism is a chronic disease with a staggering impact on society, costing the nation approximately 100 billion dollars per year, an expenditure greater than the costs associated with all cancers and respiratory diseases combined (Whiteman 2000). Large public hospital emergency department studies have demonstrated the enormous strain of alcohol use on resources, and the disproportionate burden that the care of the alcohol abusing patient places on the emergency medical system and the ED (Zook 1980). In one observational cohort, 24% of adult patients brought to the ED by ambulance were determined to likely suffer from alcoholism, further underscoring the tremendous frequency of this disease (Whiteman 2000).Interventions and therapies to mitigate the impact of alcoholism on the ED and its patients have been examined before, including the use of IV fluids to speed sobriety and the utility of the “banana bag” for the acutely intoxicated or chronic alcoholic. It is well known that people who are alcohol-dependent are prone to thiamine deficiency because of decreased dietary intake and effects on thiamine transport, storage, absorption, and utilization (Rees 2013). Alcohol consumption causes both decreased liver storage as well as decreased intestinal absorption. Prolonged thiamine deficiency can lead to alcoholic polyneuropathy, Beriberi, Wernicke’s Encephalopathy, and Korsakoff’s Syndrome. The administration of intramuscular (IM) thiamine to ED patients with chronic alcoholism is a common and reasonable practice, however the subsequent initiation of outpatient thiamine supplementation is wildly variable, and the benefit of oral thiamine therapy (OTT) is unknown.

Expert opinion has long held that prophylactic vitamin supplementation (classically, oral thiamine hydrochloride, 100mg tid for 2-4 weeks) should be prescribed to individuals identified as at risk for thiamine deficiency and Wernicke-Korsakoff Syndrome (Morgan 2015) (Achunine 2012). These recommendations have largely been driven based on estimates of what might constitute a high dose relative to nutritional requirements, however this has been called into question, as parenteral administration of thiamine is unanimously considered the route of choice to replenish stores and preclinical studies and case series have consistently demonstrated an over 80% reduction in GI uptake of thiamine in malnourished alcoholics, prompting circumspection regarding the utility of oral supplementation (Agabio 2005).

Clinical Question:

• What literature exists regarding the use of oral thiamine therapy in chronic alcoholics to prevent sequelae of prolonged thiamine deficiency?
• What relevant guidelines apply to the initiation of outpatient oral thiamine therapy from the emergency department?

Literature Review:

A PubMed and MEDLINE search was undertaken to identify relevant clinical and pre-clinical trials examining the use of OTT. Four studies were identified as applicable, including two clinical trials, one blinded pre-clinical study, and one retrospective review.

Study #1: Smithline, Donnino, and Greenblatt. BMC Clin Pharm, 2012

• Methods: Randomized, double-blind, single-dose, 4-way crossover study examining plasma levels of thiamine.
• Population: 12 healthy subjects
• Intervention: Oral administration of 100mg, 500mg, or 1500mg of thiamine hydrochloride
• Controls: Placebo
• Outcome:Plasma levels of thiamine increased nonlinearly and rapidly with oral thiamine supplementation up to 1500mg daily.
• Limitations:Neither tissue levels nor biological effects were measured, and while no side effects were reported, the study was not designed to detect adverse events. Most saliently, this study was performed in healthy patients without the presumed intestinal malabsorption of thiamine, limiting its applicability to the population in question.
• Take Home Point:In healthy patients, high blood levels of thiamine can be achieved rapidly with OTT and is not saturable up to 1500mg daily.

Study #2: Talbot. J Correct Health Care, 2011

• Methods: Retrospective review examining progression to and resolution of symptoms consistent with Wernicke’s disease.
• Population: 19 patients identified with alcohol withdrawal at intake to jail
• Intervention: Oral thiamine, 100mg PO daily for 30 days
• Controls: None
• Outcome:Early initiation of OTT hastened recovery from alcohol withdrawal and corrected excited delirium states consistent with Wernicke’s disease.
• Limitations:This was a retrospective examination of a withdrawal protocol initiated in a corrections facility and extremely limited by inconsistencies in patient assessment, lack of comparisons or controls, and variations in therapies.
• Take Home Point:OTT may be associated with improvement in thiamine-deficient states, however this study’s many limitations markedly limit its applicability to current practice.

Study #3: Rees and Gowing. Alcohol Alcohol, 2013

• Methods: Non-randomized clinical trial examining plasma levels of thiamine.
• Population: 100 alcohol-dependent patients entering an inpatient service for the management of alcohol withdrawal
• Intervention: Intramuscular thiamine (250mg) once, followed by OTT, 100mg tid for five days.
• Controls: Healthy controls
• Outcome:Thiamine levels in alcoholics were ~25% lower than control group prior to supplementation. At discharge, intervention arm thiamine levels were significantly higher than in the control group (~38%).
• Limitations:Patients received directly-observed therapy in the setting of inpatient detoxification, eliminating confounders of noncompliance and continued alcohol abuse and malnourishment. Additionally, all patients received a single dose of parenteral thiamine.
• Take Home Point:In patients under supervised withdrawal and detoxification, OTT rapidly increases plasma thiamine levels.

Study #4: Peters, et al. Alcohol Alcohol, 2006

• Methods: Multi-center, randomized, double-blind, placebo-controlled study examining symptoms of alcoholic polyneuropathy over a 12-week treatment period.
• Population: 325 patients with sensory symptoms and signs of alcoholic polyneuropathy.
• Intervention: Oral vitamin B complex formulations containing 250mg of thiamine hydrochloride taken three times daily for 12 weeks.
• Controls: Placebo
• Outcome:There was a statistically significant increase in vibration perception threshold, sensory function, coordination, reflex responses, and secondary efficacy endpoints in patients receiving OTT as compared to placebo.
• Limitations:Plasma thiamine levels were not measured. Other B vitamins (B2, B6, B9, and B12) were included in the formulations and could theoretically skew results.
• Take Home Point:Prolonged high-dose OTT significantly improves signs and symptoms of alcoholic polyneuropathy associated with thiamine deficient states.

Guidelines:

The National Institute for Health and Clinical Excellence (NICE) Guidelines recommend that oral thiamine should be given to harmful or dependent drinkers who are malnourished or at risk for malnourishment (O’Flynn 2011). The British Association for Psychopharmacology guidelines, updated in 2012, state that “if there is any suggestion that alcohol-dependent individuals may not have a healthy diet, or have reduced thiamine levels, oral thiamine should be considered” (Lingford-Hughes 2012).

Takeaway:

There are no high-quality data comparing durations, dosages, or efficacy of OTT for chronic alcoholics and those at risk for thiamine deficiency and the clinical consequences of same. It is likely that a theoretical hierarchy of dosing and frequencies exist, with parenteral superior to oral administration and multiple daily and high-dose supplementation superior to single daily doses (Isenberg-Grzeda 2014). Plainly put, there are no compelling data to inform our practice—we simply don’t know the best dose, duration, or design for OTT.

Recommendation:

Given the staggering burden of disease and inherent nonparticipation in primary care of chronic alcoholics presenting to the emergency department, as well as the trivial cost, lack of harm, and potential benefit of prescribed oral thiamine therapy, we recommend prescription of thiamine hydrochloride, 100mg tid, as ongoing supplementary therapy in alcoholic patients identified as at risk for thiamine deficiency—that is, those with clinical evidence of malnutrition (weight loss, poor healing, lack of coordination), alcoholic liver disease, or daily alcohol abuse. This recommendation is not meant to supplant, but rather augment, the routine administration of IM thiamine while patients are in the ED. Therapy should be continued for as long as risk factors persist. We recognize the significant limitation of noncompliance in this population, however believe that the potential benefit far outweighs the minimal time and resource cost of oral therapy.

References:

1. Whiteman, Paula J., Robert S. Hoffman, and Lewis R. Goldfrank. “Alcoholism in the emergency department: an epidemiologic study.” Academic Emergency Medicine7.1 (2000): 14-20. PMID: 10894237
2. Zook, Christopher J., and Francis D. Moore. “High-cost users of medical care.” New England Journal of Medicine302.18 (1980): 996-1002. PMID: 6767975
3. Rees, Ellen, and Linda R. Gowing. “Supplementary thiamine is still important in alcohol dependence.” Alcohol and alcoholism48.1 (2012): 88-92. PMID: 23161892
4. Morgan, Marsha Y. “Acute alcohol toxicity and withdrawal in the emergency room and medical admissions unit.” Clinical Medicine15.5 (2015): 486-489. PMID: 26430192
5. Achunine, Godwin, and David M. Taylor. “Drugs for alcohol dependence.” Medicine40.12 (2012): 686-687. (DOI).
6. Agabio, Roberta. “Thiamine administration in alcohol-dependent patients.” Alcohol and alcoholism40.2 (2004): 155-156. PMID: 15550446
7. Smithline, Howard A., Michael Donnino, and David J. Greenblatt. “Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects.” BMC clinical pharmacology12.1 (2012): 4. PMC: 3293077
8. Rees, Ellen, and Linda R. Gowing. “Supplementary thiamine is still important in alcohol dependence.” Alcohol and alcoholism48.1 (2012): 88-92. PMID: 23161892
9. Peters, T. J., et al. “Treatment of alcoholic polyneuropathy with vitamin B complex: a randomised controlled trial.” Alcohol and alcoholism41.6 (2006): 636-642. PMID: 16926172
10. O’Flynn, Norma. “Harmful drinking and alcohol dependence: advice from recent NICE guidelines.” Br J Gen Pract61.593 (2011): 754-756. PMC: 3223772
11. Lingford-Hughes, Anne R., et al. “BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP.” Journal of Psychopharmacology26.7 (2012): 899-952. PMID: 22628390
12. Isenberg-Grzeda, Elie, Brenda Chabon, and Stephen E. Nicolson. “Prescribing thiamine to inpatients with alcohol use disorders: how well are we doing?.” Journal of addiction medicine8.1 (2014): 1-5. PMID: 24343128

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami) and Salim Rezaie (Twitter: @srrezaie)

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