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Potential for Interactions Between Dietary Supplements and Prescription Medications

      Abstract

      Purpose

      The objective of this study was to assess the frequency of clinically significant interactions caused by concurrent use of dietary supplements and prescription medication.

      Methods

      We conducted a cross-sectional, point-of-care survey and combined the findings with a review of patient medical records. Patients treated at Mayo Clinic (Rochester, Minn) in 6 different specialty clinics were surveyed for their use of dietary supplements. Concurrent use of prescription medications was obtained from patients’ medical records. We used the Lexi-Interact online medication and dietary supplement interaction analysis program to assess the potential clinical significance of each interaction.

      Results

      We surveyed 1818 patients; 1795 responded (overall response rate of 98.7%) and 710 (39.6%) reported use of dietary supplements. In total, 107 interactions with potential clinical significance were identified. The 5 most common natural products with a potential for interaction (garlic, valerian, kava, ginkgo, and St John’s wort) accounted for 68% of the potential clinically significant interactions. The 4 most common classes of prescription medications with a potential for interaction (antithrombotic medications, sedatives, antidepressant agents, and antidiabetic agents) accounted for 94% of the potential clinically significant interactions. No patient was harmed seriously from any interaction.

      Conclusions

      A small number of prescription medications and dietary supplements accounted for most of the interactions. The actual potential for harm was low.

      Keywords

      Complementary and alternative medicine treatments are used by more than two-thirds of the US population, and dietary supplements are some of the most popular treatments.
      • Barnes P.M.
      • Powell-Griner E.
      • McFann K.
      • Nahin R.L.
      Complementary and alternative medicine use among adults: United States, 2002.
      Most of these treatments are not regulated tightly by the US Food and Drug Administration and are available without a prescription from a physician. Several treatments have the potential for adverse effects, including medication interactions.
      • Use of dietary supplements is common in the US population.
      • Despite a high prevalence of potential interactions between dietary supplements and prescription medications, the actual potential for harm is low.
      • A small number of prescription medications and dietary supplements account for most potential interactions.
      • Antithrombotic medications were most likely to interact with dietary supplements.
      Dietary supplements typically have multiple active pharmacologic constituents. Thus, the likelihood of interactions is increased when compared with the likelihood of interactions between 2 prescription medications.
      • Izzo A.A.
      Herb-drug interactions: an overview of the clinical evidence.
      Currently, most interactions involving dietary supplements are reported as case series or individual case reports.
      • Williamson E.M.
      Interactions between herbal and conventional medicines.
      • Izzo A.A.
      • Ernst E.
      Interactions between herbal medicines and prescribed drugs: a systematic review.
      • Fugh-Berman A.
      Herb-drug interactions.
      • Hu Z.
      • Yang X.
      • Ho P.C.
      • et al.
      Herb-drug interactions: a literature review.
      The actual potential for interaction in a large group of patients is not well understood.
      This study was designed to assess the most common clinically significant interactions among patients who concurrently use dietary supplements and prescription medications. The study involved a point-of-care survey of patients treated in 6 different specialty clinics. The potential for interactions was defined on the basis of published evidence of interactions.

      Patients and Methods

      Survey

      An 85-question survey was designed to determine the use of complementary and alternative medicine therapies during the 6 months before the survey date. Survey questions examined use of 52 listed dietary supplements, and a text entry field was provided for patients to document use of supplements not included in the survey. Details of the survey have been described previously.
      • Wahner-Roedler D.L.
      • Elkin P.L.
      • Lee M.C.
      • et al.
      Complementary and alternative medicine: use by patients seen in different specialty areas in a tertiary-care centre.
      • Wahner-Roedler D.L.
      • Elkin P.L.
      • Vincent A.
      • et al.
      Use of complementary and alternative medical therapies by patients referred to a fibromyalgia treatment program at a tertiary care center.
      Briefly, a point-of-care survey was administered to 1818 patients in 6 different specialty clinics at Mayo Clinic (Rochester, Minn) from September 2002 through July 2003. The 6 specialty clinics were the Departments of General Internal Medicine, Oncology, and Physical Medicine; the Fibromyalgia Clinic; the Preoperative Clinic; and the Spine Center. These 6 specialties were chosen because of the high volume of patients and because the patients in these specialties were more likely to use complementary and alternative medicine treatments.
      A study assistant was available to answer questions and facilitate survey completion. Dietary supplements were defined as products containing herbs or other botanical components, amino acids, enzymes, organ tissues, glandular extracts, or metabolites. Vitamins and minerals were not included in this definition. Prescription medications were defined as pharmacologic agents that were available in the United States only by prescription from a physician. Aspirin also was included in this definition. For the purpose of this study, we analyzed the responses about the use of 52 listed dietary supplements separately from the additional products listed by the patients in the free text area. Informed consent was obtained from each patient, and the study was approved by the Mayo Clinic Institutional Review Board.

      Use of Prescription Medication

      Patients at Mayo Clinic have a single integrated medical record that is shared by all health care providers, thus ensuring complete and consistent data about the prescription medication usage. The patient medical records were reviewed by 3 study investigators (AS, RS, DLW-R) after confirming research authorization for each patient. We examined concurrent use of prescription medication during the 6-month period covered by the survey of dietary supplement usage. Medical records also were reviewed to determine whether any patient was seriously harmed as the result of an interaction between the dietary supplement and prescription medication. Serious harm was defined as hospitalization for aggravation of any underlying medical condition or for a new medical problem that was a direct result of the interaction.
      Electronic medical information was available for all patients who completed the survey. We collected baseline data, which included patient demographics, self-perceived stress level (scale, 1-5; 5 was the highest level of stress), and number of symptoms checked on the review of systems questionnaire, a standard part of our electronic medical record. An individual case report form was created for each participant. On the basis of the participants’ reported use of dietary supplements, each report included the list of potential dietary supplement–medication interactions.

      Potential Medication Interactions

      The information on the potential interactions was obtained by searching the MEDLINE database (using PubMed),
      Entrez PubMed National Center for Biotechnology Information.
      the Natural Medicines Comprehensive Database,
      Natural Medicines Comprehensive Database Stockton, CA: Therapeutic Research Faculty, c1995-2007.
      and a published textbook.
      • Brinker F.J.
      Herb Contraindications and Drug Interactions: With Extensive Appendices Addressing Specific Conditions, Herb Effects, Critical Medications, and Nutritional Supplements.
      Interactions from the Natural Medicines Comprehensive Database were included if a published reference was available. In the MEDLINE searches, we used generic names of the supplements as key search terms. All clinical trials, case reports, and case series for each product were reviewed to create a master list of potential medication interactions. The potential for interaction between 2 dietary supplements was not considered in this study because of the relatively limited evidence-based information about these interactions.

      Clinical Significance of Interactions

      Clinical significance of individual interactions was assessed using the Lexi-Interact online medication and dietary supplement interaction analysis program, which provided up-to-date information.
      Lexi-Comp Online Hospital/Institutional Solutions. Lexi-Comp, Inc.; c2007.
      The program provided a summary of medication interactions with an assigned risk rating (range, A-D and X). The risk rating and its interpretation were as follows: A=no known interaction; B=no action needed (potential for interaction but of no clinical significance); C=monitor therapy (potential for interaction that may be of clinical significance and needs monitoring); D=consider therapy modification (potential for interaction that may be of clinical significance and needs close monitoring, change in therapy, or both); and X=avoid combination.

      Data Analysis

      Differences in baseline characteristics between participants who did and did not report use of dietary supplements were compared using the chi-squared and log-rank tests. P values <.05 were considered statistically significant. Statistical analysis was performed using the SAS software package, version 9.1.3 (SAS Institute, Cary, NC).

      Results

      Survey Response Rate

      The overall response rate to the survey was 98.7% (1795/1818). Of the 1795 respondents, 710 patients (39.6%) reported use of dietary supplements. These data were reported previously.
      • Wahner-Roedler D.L.
      • Elkin P.L.
      • Lee M.C.
      • et al.
      Complementary and alternative medicine: use by patients seen in different specialty areas in a tertiary-care centre.
      • Wahner-Roedler D.L.
      • Elkin P.L.
      • Vincent A.
      • et al.
      Use of complementary and alternative medical therapies by patients referred to a fibromyalgia treatment program at a tertiary care center.
      Eleven patients did not have information about the use of prescription medications in their electronic medical records, and those patients were excluded from the interaction analysis. Thus, the final sample comprised 699 patients. Of these, the medical records of 185 (26.5%) showed use of dietary supplements.

      Baseline Comparisons

      The mean ages were similar between participants using dietary supplements and participants not using these products (Table 1). Women were more likely to use dietary supplements than men. Patients using dietary supplements had more symptoms on the review of systems than patients not taking these products. The mean stress level was statistically different between the 2 groups (P=.008), but the actual difference of 0.1 was not clinically meaningful. The mean number of prescription medications per patient was not significantly different between the 2 groups (P=.71).
      Table 1Baseline Characteristics
      CharacteristicUse of Dietary Supplements
      Excludes use of vitamins and minerals.
      Yes (n=710)No (n=1085)P Value
      P values were calculated by comparing means only.
      Age, years.56
       Mean±SD55.7±14.958.1±16.8
       Median (range)58.5 (18-90)59.0 (18-95)
      Sex, no. (%).003
       Men (n=704)248 (35)456 (65)
       Women (n=1091)462 (42)629 (58)
      Specialty, no. (%)
       General internal medicine (n=308)103 (33)205 (67)
       Oncology (n=304)123 (40)181 (60)
       Physical medicine (n=295)94 (32)201 (68)
       Fibromyalgia147 (51)141 (49)
       Preoperative clinic (n=302)127 (42)175 (58)
       Spine center (n=298)116 (39)182 (61)
      Stress level
      Self-perceived stress level was rated from 1 (low) through 5 (high).
      .008
       Mean±SD3.0±1.12.9±1.1
       Median (range)3.0 (1-5)3.0 (1-5)
      Symptoms, no.<.001
       Mean±SD10.6±8.69.1±7.7
       Median (range)9.0 (0-59)7.0 (0-46)
      Prescription medications, no..71
       Mean±SD3.6±3.13.7±3.3
       Median (range)3.0 (0-18)3.0 (0-22)
      low asterisk Excludes use of vitamins and minerals.
      P values were calculated by comparing means only.
      Self-perceived stress level was rated from 1 (low) through 5 (high).

      Potential Medication Interactions

      The most common dietary supplements with a potential for interaction were garlic, valerian, kava, ginkgo biloba, St John’s wort, glucosamine, ginger, and ginseng (Table 2). The most common prescription medication classes with a potential for interaction were antithrombotic medications, sedatives, antidepressant agents, and antidiabetic agents (Table 3). In total, 369 potential interactions were identified among 236 patients. Of these, 107 interactions were considered to have potential clinical significance (risk rating of C or D) (Table 2). No potential interactions resulted in serious harm to any patient during the study period.
      Table 2Potential Interactions of Dietary Supplements and Prescription Medications
      Excludes use of vitamins and minerals.
      Dietary SupplementPrescription MedicationRisk Category C, No. of Patients
      Potential interactions in this category may have clinical significance. Patients should be monitored.
      Risk Category D, No. of Patients
      Potential interactions in this category may have clinical significance. Patients should be monitored closely or have the therapy modified.
      GarlicAntiplatelet agent22
      Warfarin3
      ValerianSedative15
      KavaSedative7
      Hepatotoxic medication3
      Ginkgo bilobaAntiplatelet agent9
      Warfarin1
      St John’s wortAntidepressant agent8
      Tramadol1
      Oral contraceptive1
      GlucosamineWarfarin9
      GingerAntiplatelet agent7
      GinsengAntidiabetic agent6
      BilberryAntidiabetic agent3
      Evening primrose oilAntiplatelet agent2
      FeverfewAntiplatelet agent2
      TumericAntiplatelet agent2
      5-hydroxy-l-tryptophanAntidepressant agent2
      Dong quaiAntiplatelet agent1
      HawthorneAntihypertensive agent1
      Olive leafAntihypertensive agent1
      Pau d’arcoAntiplatelet agent1
      low asterisk Excludes use of vitamins and minerals.
      Potential interactions in this category may have clinical significance. Patients should be monitored.
      Potential interactions in this category may have clinical significance. Patients should be monitored closely or have the therapy modified.
      Table 3Prescription Medications That Commonly Showed Clinically Significant Interactions with Dietary Supplements
      Excludes use of vitamins and minerals.
      Medication ClassNo. of Patients
      Antithrombotic medication
       Warfarin13
       Antiplatelet agent46
      Sedative22
      Antidepressant agent10
      Antidiabetic agent
       Insulin3
       Oral medication6
      Other
      Antihypertensive agents, hepatotoxic medications, oral contraceptives, and tramadol.
      7
      low asterisk Excludes use of vitamins and minerals.
      Antihypertensive agents, hepatotoxic medications, oral contraceptives, and tramadol.

      Discussion

      Principal Findings

      The present study showed that approximately 2 of 5 surveyed patients reported use of dietary supplements. In total, 369 potential interactions were identified among 236 patients. Of these interactions, only 107 (29%) had potential clinical significance. The 5 most commonly used dietary supplements with a potential for interaction accounted for 68% of all possible interactions. The 4 most common prescription medication classes with a potential for interaction accounted for 94% of the possible interactions. No patient had serious harm from the possible interactions during the study period (ie, no patient was hospitalized for an aggravated underlying medical condition or for a new medical problem that was caused by an interaction). Use of dietary supplements was documented in only 26% of the medical records.

      Study Strengths and Weaknesses

      The study had several strengths, including large sample size, excellent response rate to the survey, inclusion of patients from different specialty groups, and availability of complete data for most patients. These strengths increase our confidence in the validity of the study results.
      Our study had several weaknesses. First, like most surveys, ours did not eliminate the possibility of recall bias. Recall bias was minimized, however, by providing the participants with the names of all commonly used products. Second, the medical record information about prescription medication use may have been incomplete or inaccurate. To increase the accuracy, we checked for documentation from multiple care providers at our institution and from patient-provided information that was scanned into the medical records (each patient at Mayo Clinic has a single integrated electronic medical record). We also were able to obtain clinical data and a current list of medications for 98.5% of our patients (699 of 710), thus increasing the validity of our findings. Third, the existing information about potential interactions between dietary supplements and prescription medications was incomplete. We relied primarily on the medical literature to identify adverse interactions documented in humans. However, these interactions may not always be a direct effect of a dietary supplement and could be an effect of adulterants in the supplement (eg, heavy metals or pesticides), prescription medications, or misidentified plants.
      • Ko R.J.
      Adulterants in Asian patent medicines.
      • Fugh-Berman A.
      • Ernst E.
      Herb-drug interactions: review and assessment of report reliability.
      • Tyler V.E.
      Product definition deficiencies in clinical studies of herbal medicines.
      • But P.P.
      Herbal poisoning caused by adulterants or erroneous substitutes.
      • Gertner E.
      • Marshall P.S.
      • Filandrinos D.
      • et al.
      Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs.
      Finally, even though we surveyed patients in 6 specialty clinics, the generalizability of our study findings to the community setting might be limited.

      Comparison with Other Studies

      Use of dietary supplements is extremely common in the United States. In the largest point-of-care, population-based survey to date, of 31,044 surveyed patients, 18.9% reported use of dietary supplements.
      • Barnes P.M.
      • Powell-Griner E.
      • McFann K.
      • Nahin R.L.
      Complementary and alternative medicine use among adults: United States, 2002.
      The higher proportion of 39.6% in our study likely resulted from a combination of referral bias and inclusion of patients with medical conditions such as cancer, fibromyalgia, and chronic pain, which increased the likelihood of use of dietary supplements.
      In 1999, a point-of-care survey asked 458 veteran outpatients about their current use of dietary supplements.
      • Peng C.C.
      • Glassman P.A.
      • Trilli L.E.
      • et al.
      Incidence and severity of potential drug-dietary supplement interactions in primary care patients: an exploratory study of 2 outpatient practices.
      Intake of prescription pharmaceuticals was identified through a Veterans Administration pharmacy database search. A total of 197 patients reported using dietary supplements. The potential for prescription medication–dietary supplement interaction existed in 45% of these patients (89/197). The higher estimate obtained in that study likely is attributable to the inclusion of vitamins and minerals when considering possible interactions. The most common products with a potential for interaction in that study are among the most likely products for interaction in the present study (ie, garlic, ginseng, and gingko biloba).
      Other studies have documented concurrent use of herbal products and prescription medications. In a national survey conducted in the United States, concurrent use of herbal remedies and prescription medications was documented in 18.4% of prescription medication users.
      • Eisenberg D.M.
      • Davis R.B.
      • Ettner S.L.
      • et al.
      Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.
      However, the potential for interactions was not addressed. In a British study involving 271 participants older than 50 years, a mean of 5.91 supplements and a mean of 2.26 prescription medications were used concurrently.
      • Canter P.H.
      • Ernst E.
      Herbal supplement use by persons aged over 50 years in Britain: frequently used herbs, concomitant use of herbs, nutritional supplements and prescription drugs, rate of informing doctors and potential for negative interactions.
      However, a specific evaluation of the potential for interactions was not reported. In a smaller survey of 76 patients with cancer, 27% were reported to have a potential for herbal products or vitamins interacting with chemotherapeutic agents.
      • McCune J.S.
      • Hatfield A.J.
      • Blackburn A.A.
      • et al.
      Potential of chemotherapy-herb interactions in adult cancer patients.
      In a Canadian study of 195 patients older than 65 years, 33 current users of herbal medicines were identified.
      • Dergal J.M.
      • Gold J.L.
      • Laxer D.A.
      • et al.
      Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic.
      Among those patients, 11 potential herb-medication interactions were identified in 9 patients (27%). In a Canadian study involving seniors with osteoarthritis, 214 potential interactions were identified. Of these, 30 were considered clinically significant.
      • Putnam W.
      • Lawson B.
      • Frail D.
      • et al.
      Potential for drug interactions in seniors with osteoarthritis.
      Among all prescription medications, antithrombotic agents are the best-described class of medications with a potential for interacting with herbal products.
      • Heck A.M.
      • DeWitt B.A.
      • Lukes A.L.
      Potential interactions between alternative therapies and warfarin.
      • Norred C.L.
      • Brinker F.
      Potential coagulation effects of preoperative complementary and alternative medicines.
      In a study involving a search of electronic databases, warfarin was the most common medication documented to have a potential for interaction with herbal products.
      • Fugh-Berman A.
      • Ernst E.
      Herb-drug interactions: review and assessment of report reliability.
      Findings from the present study, which surveyed a broad patient population, confirmed that antithrombotic medications indeed were the ones most likely to interact with dietary supplements. However, the actual potential for harm in quantitative terms is unknown because well-designed studies to evaluate adverse effects would be unethical and not feasible. Until further data are available, patients receiving antithrombotic medications generally should be counseled to avoid dietary supplements known to interact with warfarin or known to have an antiplatelet effect.
      Distinguishing between a real potential for harm and a purely speculative interaction is important. Despite a high prevalence of the potential for interaction, no serious adverse events such as hospitalization or serious bleeding due to interactions were documented in any of our patients. Some interactions that were included in the study could be considered speculative. However, it might be prudent to take a balanced but cautious approach, even if some cause-and-effect relationships are not well established, and particularly if the purported treatments are not proven to have a beneficial biologic effect. Furthermore, dietary supplements often are intended to be taken for long periods, and given the high prevalence of their use, even a small potential for harm might have public health consequences.
      In summary, the present study showed that a small number of prescription medications and dietary supplements accounted for most potential interactions. This information likely will help educate patients and physicians about these potential interactions.

      Acknowledgment

      Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.

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