Natural health product reporting with concurrent benzodiazepine use: A Systematic Review

Baljit Khamba, andace Necy!, "enise Adams, Sunita #ohra

BACKGROUND

AR$ %rogram o& 'ntegrative (ealth ) (ealing, "epartment o& %ediatrics, *niversity o& Alberta, $dmonton, Alberta, anada

RESULTS

DISCUSSION

Benzodiazepines promote calming due to their potentiating e&&ect on the inhibitory neurotransmitter 0ABA +hey are widely prescribed to treat a variety o& conditions, most notably an-iety and insomnia Some natural health products 1N(%s2 can also in&luence neurotransmitters, including 0ABA, leading to a potential N(%/drug interaction

H@C Re&erences identi&ied through searches

<HC Re&erences remain

E@ duplicates removed ;C@ e-cluded a&ter titlesKabstracts screen <@A e-cluded because o& lac! o&: Availability o& &ull article 1442 $nglish article 1A2 7utcome o& interest 1;<2 %rimary report 1<<2 Single herb 1<;2

5E Articles included

OBJECTIVE
(uman

Non/(uman

+o investigate interactions between benzodiazepines and natural health products

;R +

; ase Reports

4C

METHODS

459 total articl ! "cl#$ $

+he &ollowing databases were searched &rom their inception &or terms related to benzodiazepines, N(%s, adverse events or interactions: 3edline, $mbase, and ochrane entral Registry o& ontrolled +rials, Selection criteria included published $nglish language studies, o& any design, and in all populations, Re&erences were screened by ; reviewers, Studies that reported an interaction between a benzodiazepine and N(% were included, "ata about the interaction 1including possible 6% interactions2, drug, N(%, and study population were systematically e-tracted by ; reviewers, %ercentages and proportions o& dichotomous data were calculated based on whether an A$ occurred or not, $ach A$ was &urther subclassi&ied by the type o& interaction category 1blue, yellow, orange, and purple2 Blue: No reported or theoretical interaction 6ellow: +heoretical interaction e-trapolated &rom animal or in vitro data 7range: +heoretical interaction e-trapolated &rom clinical data %urple: 'nteractions supported by clinical evidence

.igure <: .low o& re&erences through review

Benzodiazepine Blue "ntera#tion 5es 8o Total

Benzodiazepine Blue Type All Alprazolam Diazepam Midazolam Lorazepam Bromazepam Oxazepam Phenazepam Total

Yellow 1 4 5
Yellow 9 1 2 2 17 11

Orange -6 4 3
Orange

$ed 7 6
Purple

Total 3
Total 9 6 20 16 1 1 1 1 55

0 ! !

4 1 2 1 1 1 10

1 1

37

1 3

RESULTS

5E articles met inclusion criteria 7& the included studies, << involved human populations 1; randomized controlled trials, C controlled trials and ; case reports2 45 articles were controlled trials using animal or in vitro e-periments 5@ articles suggested an interaction had theoretically or actually occurred while E articles indicated no interaction, 'ndividual reports o& benzodiazepine interaction indicated predominant interactions occurred as 8yellow9 14C2 or 8orange9 1<@2, Botanical N(%s revealed similar results with 5@ in the 8yellow9 category and E in the 8orange9 Results indicate predominant theoretical interaction A chi/s:uared test o& independence was per&ormed to e-amine the relation between N(%s and type o& interaction, +he relation between these variables was signi&icant, F;14,

NHP Blue Acetea Racemosa Allium ati!um Alo"sia pol"stach"a Am#rosia paniculata An$elica dahurica Anisomeles mala#arica Aspalathus linearis Azadirachta %ndica Bacopa Monniera Ben&ara mala#arica Bridelia 'erru$inea (amellia sinensis) (innamomum cassia ("m#opo$on citratus *leuthroccus senticosus +lue$$ea !iosa ,anderma lucidum ,elsemium semper!irens ,in&$o #ilo#a ,uiera sene$alanis .umulus lupulus ."pericum per'oratum Panax ,insen$ Panax /uin/e'olium Papa!er somni'era 0 rhoeas Piper meth"sticum Psoropermum sene$alense Ptelepsis su#ersa) Rollinia mucosa Rosa damascena Ru#us sua!issimus al!ia miltiorrhiza enna pecta#ilis 1erminalia macrtera 1ernstreomia prin$lei 2alerian O''30 edulis 2itis !ini'era 4ithania somni'era Total

Yellow 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Orange 1

Purple

Total 1 2 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1 5 1 2 6 2 1 2 2 1 1 1 1 1 2 1 1 1

+his study identi&ied interactions between benzodiazepines and N(%s, (owever, a signi&icant majority indicated that the interactions were theoretically based Both "iazepam and 3idazolam, long and short acting benzodiazepines, respectively, signi&icantly interacted with N(%s Nine articles discussed theoretical interactions o& all benzodiazepines through the metabolic enzyme, cyctochrome %4A5 1 6% 4A52, +his enzyme is involved in the metabolism o& not only benzodiazepines, but many other drugs that &all into a similar reaction class 0ing!o Biloba was shown to have the most reported adverse events 1theoretical or otherwise2, &ollowed by #alerian 7&&icinalis and (ypericum %er&oratum, .urther clinical research is warranted especially &or these three botanicals, +he majority o& the data indicated a 8yellow9 interaction response, suggesting that there are potentials &or adverse events to occur between the substances in :uestion, +he identi&ication o& &ew 8purple9 responses may be due to reasons such as no A$ occurred, lac! o& identi&ication o& A$ by patients or practitioners or lac! o& publication o& A$ in&ormation, Benzodiazepine interaction with N(%s were more li!ely to be theoretical, as opposed to those shown in clinical studies, 3ore research to determine the clinical signi&icance o& theoretical interactions is needed,

CONCLUSIONS
+heoretical data suggest multiple potential interactions between N(%s and benzodiazepines are possible, (owever there is a lac! o& concrete clinical data that would de&initively determine i& true adverse events e-ist .urther clinical data are urgently needed to determine i& such interactions are clinically relevant, and to guide patients and health care providers regarding concurrent use $ducating the public and health care practitioners about the potential &or N(%/drug interactions may increase the pool o& in&ormation about A$s and provide more convincing data about the occurrence o& A$s in clinical care,

1 1 1 1 1 2 1 1 1 1

1 1 1 1

1 1 1 1 1 2 1 1 1 1 1 0

REFERENCES
<2 vijovic, ,, Boon, (,, Barnes, =,, Brulotte, =,, =aeger, >,, 3urty, 3, #u, ",, Reid, S,, #ohra, S, A tool &or rapid identi&ication o& potential herbal medicine?drug interactions, Canadian Pharmacists Journal ;@@AB<5;: ;;5/;;C ;2 Stargrove 3B, +reasure =, 3cKee "D, (erb, Nutrient, and "rug 'nteractions, <st ed, St Douis, 37: 3osby $lseiverB ;@@E,

1 1 1 57

.igure ;: Reported interactions and their categorical designation

ACKNO%LEDGEMENTS
S# receives salary support &rom Alberta 'nnovates / (ealth Solutions