DEPT, OF ANAESTHESIA KKUH 4679364

SEDATION CHARACTERISTICS OF MELATONIN AND MIDAZOLAM FOR PREMEDICATXON OF ADULT PATIENTS UNDERGOING CATARACT

SURGERY UNDER LOCAL ANAESTHESIA

RANA AI.TAF ~d', FCPS, ABI>ULHAMLD AL-$ABED, FFARCSI, SMR M. AL-MANSOURI', MBBS, KSUF, SALEH A. AL OBELDAN~, MD

This praapcctive. double blind pl.cekn cnn*llrnl phdy iia dori#mod m cnmpam the eReota of sublingunl molatonin vemua rnidrvalarn for pmrncdicstion of d u l l patimb schadulod to cntanct auruery under local anaaatheain. Seventy fivs pntiarts ASA1&2 mgad from 40.70 yr aohdulcd fnr c h . t m ~ t alurgwy prooodute warn ntudisd. Paticnte tm ck4~IIified into 3 groups. Group 1 raceivod mldazolsm, group 2 R C ~ V C ~

mclstnn~n and m u v 3 received plaoebo. Patients in gmup 1 moeivd ntrhlingnvt 0.5% midamlam nolution O,lms/lrg body wciglht. Oroup 2 mctivcd aublinaual melatoninO.O5me/kg body weight. The control p u p receivad nubllngual pIa6ebo (salino).All dmpn w e n pivan 100 min hefore L e local block. godat-inn, nn*iMy and sri&~~ation wcrc quantified bclbm end 10, 30, 60 min after prerncdicatioo and 15, 30, 60 min aftor admi~nian to the rrrauvcv mom. One way ANOVA and nnn-parametric Kurehl-walli~ tent were for rtutinlical annlysifi.

Petionrs who receivcd promdication with cithcr rnidaralam ar melatontn had ai~iiificant decrcaae In lulxiety Icvelh compared wtth c o n h i poup and midnzolntn mup aimificant increaec in level of sedatirm before operation was noticed cnmpmd with melnmnin and contml groups (p<O.OS). Midazolnm p r o d u d higheel auulcn ~~TnuJnliun nt 30 wd 60 mln nRcr ad~nlnluwtion and ei@nrficnnt p~ychomotnr rmprirmant in the pranpcrative perlod comparcd with melnton~n and placebo gmupri(p<0.05). Poatoperntivc pnlients who rccoiveA mid~~mlrm. mcl~tonin prsmrdicatirm n h m ~ d no incrcanm in level nC narlnlinn nt nll intmnll. Thcrc wan nn mknificant di f lw~cc bctwcen tho Rrollpe for anxiety Isvele ar t r i ~ ~ c r dot tontins porfomnnel &tr operatinn cnrnymwi with control @>0.05), hnvlesirr wna r r c l ai8nificsnt in hcnh the p t t p n , In nonnlusion. melatonln can ho used effeotively for premsdicstinn of adult patient1 withbut hsngov~r affact cornpad 10

rnidazolam

MmAzor.aM BELONOS TO A CLASS of bcnzodiazepine derivative characterized by rapid un~el of amionld. Following oral adrninimtlon, peak plasma concantration rises within 30 to 45 min. The onset of sedative offects has been reponcd within 15 min, with peak effect^ in 30 to 60 min. Elimination half-life &or intravenous administration w a ~ rqurted to be 2.3 h. The bioavailability after the ingest~on of 10, 20 and 40 mg midazolam in the form of a tablet ranged from 31 % to 73% due to

- .- .- - ' ~apn tment of neathe he ria, College of Mcdtoine, K ~ n g 9md Un~voretty Hoapltda '~tpa?tment nf Annaathmf* mrl '~apamntnl of Ophthalrnolom. Kina Abd~~fuziz Univer@lQ

Huuplfal, CalMga OTMddlOiM, &fig Snud Unnmtty, K~yadh. Addteen for corrcupondonce: Rann Altaf Ahmad. DA -

FCPS, Conaultnnt Anacathctlat, ICing Ahnulaiz Utlivar~~lty Hosp~tal, P.O. Box 2 4 5 , R~yndh 11411, K ~ l l ~ d ~ j m uf Suudi Arahia

E-mail: drranaaltaff@y~h~~o.c~m

extonaive first pass hepatic extraction of midm~lam'~. The pineal hormone melatonin (n- ~catyl-9-methoxytryptnmine) hoa acvcral putative functions including regulation nf c i ~ l d i ~ n rhythms, rcaulahon of the reproductive axis, and antioxidant

2.3) . Auto rad~ngraphic qhldie~ and receptor assays have demonstrated the preRence of mel~~onin receptors in vaqo~~s regions of the central nervous sywtem and in other tissues in humansa. Exogenou~ alimtnlskatian of meltatonin has been found by several investipators to facilitate sleep onset and improve quality of slbbp (" '). Available data suggest that the elaep inducing propertie# of melatonin may differ from those of benzodiazqinoa. Benzodiazaplne , derivative mducefi duration of (REM) sleep after single administration of high dose or long time administration of low done ('I ". Benzodiazopine also reduce slow wave sleep thus negatively infli~encing sloop quality but in contrast ~ i n g l e d n ~ a mslrtgnin produce no flupprtsaion of REM sleep and there is no hangover effects like

Saudi Jamr) ofPurseahak Vol 1. Na l.AprIlZW7

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CHARACTERISTICS OF MELATONIN AND MIDAZOLAM 21

of (n-

ative hmu, idant

.onin v- - q

1 h . e

1 by and

%eat

ines. ! of doee 7, 5).

thus .trast n of like

benz~diaze'pine~"~. This prospective, randomized, double blind placebo controlled study was conducl.acl to cdmpase the effects of sublingual melatonin versus midazolam as prmedicatinn in local anaesthesia for cataract surgery in adult patients. The sedative, anxiplytic and amncsic effects of both drugs in addition to residual etTectu in the immediate postoperative period were evaluated,

After obtaining institutional approval and informed coneant from patients, we studied 75 ASA physical statua 1,II patients, Age (40 - 70 y) wcigh 44-90 kg scheduled for cataract ,i.lrgery , Patients who were taking centmlly acting drug8 consuming monoatnine oxid~se inhibitow, or dlcrgic to study drugs were excluded. The day before study the principal investigator cxplninad the study plan and ahowed the patients the different scales used in tho macwment, Approximately 100 rnin befire surgery patients we? shiRed to an i~olnted quita room in the holding area. A pulse oximeter probe was placed on all patients and Spo2, marial blmd prafisur'u and heart rate were monitored continuously, Reswcitative equipment ww immediately available at the hed ~ ide . Patients werc allocated randomly to O I I ~ of the rhree groups (n=25 each). First group received sublingual 0.5% midazolam 0.1 mgkg . ':['he rracond group reoeivcd sublingulrl melatonin O.OSmu/kg body weieht. The third group roccived sublingual placebo (saline). Stsdy dnlga and placebo were prepared to a volume or 3ml in a syringe from which needle was removed, marked only with coded label to lk~dnrsin the double blind nature of study. The content of thc syringe wtrs given suhlingually approximately 60 min before block of the cyc by the anaesthesia technician who wa8 not involved in data collection. At 180 sec the patient will be permitted to swallov the medication, A visual at~nlogue ~ca le (VAS) wm used to wvaluaw aedation and amiety levcls. The s d e was a 50 cm long and tOcm hi& card diagonally divided to a .white and bright red Iriangle. The centimeter scale was on the rear side of the card16. The extremes am marked no sedatiodanxiety at the white end and sedatioolanxiety as bad as aver at the red end. Thc same interpreter-blinded to group aseignment- evaluated VAS for anxiety; oricntaliur~ score {O=none, l=orientation in either time or place, 2~orimtation in both); Sedation score {1- awake,

2=drowsy, 3=asleep but arousable, 4-asleep but not arousahle) before 10, 30, and 60 rnm after the administration of prembdicatio~l and postoperatively at IS. 30, 60 min aRar dmlssion to post anaesthesia care unit (PACU). Patienh were asked to perform the Lngger dot test (TDT) at theso trrnes. This test was used to quantitatively assew psychomotor activity. All patients positioned with 30 degree head elevatron and used tho aamc writing implement (ball point, medium point. black) for all teats. The TDT score representd the total number of dots (42) connected. TDT deviation rapresented the c~unulative shortcat distance in rnm between the drawn lines and missed docs to account for inter- patient differences in test taking ability. TDT scores and TDT deviations were normalized to baseline scores and deviation for each patimt. Changes ~n scores of different testa and TDT deviation and TDT time relativo to baseline values were compared. A~klne~ia was msessed by ehowing ptttienm two simple colored figures star and rectangle before plxmncdicatlou. Ptthenta were queried 24 h later as to recall of the figures. In the holding area, an inhhinn of 5% UIW wilh l/i NS was etarted. Ail the blocks were performed by the ophtbalmolagisa. Peribulbnr block was given to all patients using infer~nr and superior approach by 5n1l of Xylocalne 2"h and bupivacainc 0.5%. At aach block toleratinn to the procedure was assessed. Standard monitoring were used i.e. pulse oximetry, non invasivc blood preesure (NIBP), and blectrocardiography (ECG) (Datex- Ohuadn, Pinland).The tntraoperntive sedation and tolerance to the procedure was done by the concerned anesthetist of tho 01198. In the recovury room the same teats were repeatad. Postoperative pain was @catad wit11 injection diclofenac sodium 1- 2 mgkg b.w.

One way ANOVA was used to compare the mean values of quantitative variables acrn~s the three drug p u p a . A non-parametric Kurskal-wallis Lest was used Lo cnmpare the scores of outcollle variables across the three drug groups. A p- value eU,05 wae oonrridcrcd signifiomt.

Results

Palients in thc three groups werc comparable in age, weight, surgwy and anaesthesia times (pH.05) (Table I). Therc was no significant difference in VAS for anxiety measurement batween the groups after giving prernedication at 10, 30. 60 mln as well

Saudi ~ m m ~ o f ~ i a , Vnl 1 ,Na 1,Apilm

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RB postoparativcly at the Mame inma1 compared to baseline (p;.O.OS) (Fig 1).

Table: 1 . ConyJurison of pmlenrs ucrm fhr! rhme dnq groups In relatian to Arrc ,wlrl#bt, Mgcw tune and Anaexthesia time

a F- rvalue Varinblcs Placebo molam tonin value

, A g (yr.) 56.1 57.1 58,O 58.0 3.92

I Weight (kg.) 74.9 74.8 76.6 0.08 0.92

. I , stlrgary 57.7' 511.8 53.3 0.34 3.71 ; I i Timqrnin.) ' '1 ' I Anaeathaaia

if Time (rnin.) 83.5 83.7 76.8 0.40 9.67 ! -

O-11.l .I &l.D*r rn vmIbn!.~l lmr l ~ ~ l l ~ 1 1 . 1 1 . 1 1 L ll "hi -1

~ I n b u , I h . v h m ~ UWIIO~D t e a r r h rrhlm I . I w V A b .ma+~i r w n

., . -

Flu. I,.

&

AHMAD ET AL. CI

' , I

missed in the postoperative period between the groups (Fig. 4). Patients who were in deep sleep (asleep but not arousable) were unable to perform th? TDT and are not includ~d in the statist~cal analysis (mldamlarn group) (Table 2). Two af the patients in the midazolam group were cancelled due to deep sleep (level 4) and inability to give local pezibulbar block. In the melatonin group, none of the patients was cmcetled. In the midazolam group at 24 hr four patients did not recall the one diagram shown to thcm. In the molatonin group all patients recalled the two dlagrams shown to them. Twenty percent o f , patientfi in the miduolam woup and 22% of p~tientt in the melatonin group were satisfied witb thetr premedicalion compared with 19% in the placebo group. Tolerance to the procedure was bad in 4 cases of rn~dazolam group due to hangover cffcct. The tolerance to the procedure was good m 24 patlents in melatonin proup comnpastrcl to placebo, Pain wtlh nor expefjenced by any p~tient in rnelatonln and ' rniholam ereup. Only one pnl imt in plxcho group con~plail~ed o f pnm nnd was treated with diclnfennc ~njectirrn,

!!li!l

iii 1

M I Ar

Exb Gna

Therc wwa no sidcgnt diffemnoe in orientation score between the two groups compared with tbc bsselina in pt-eoperntivc ~ n d postoyoralive poriod

PlE Nn

mi An Exn Anx

except in two casea of midemlem, group where patients were in deep sleep nfier pre-medication and swpery has to be cancnlled (p10,05), Furthermore. patients in the midazolam group, uhnwed significanl (~0.05) high level o f sedation compared with melatonin group at 30 and 60 rnin (Fig 2). Postoperatively there was no diffemce in ltvel of sadation of groups 1 and 2 at all intervals compared with the pla~ebo group 3 (Table 2). Orientation score wav similar except at I5 and 30 rnin after premddication in midazolam p u p . At that time only 20 patientm were orientated to time and place compared to melatanin (24%) and placebo (23%) respcctivaly. Regarding psychomotor funotion, thcrc was ~ignificant. difference in performing the TDT test for the midmolm group preoperatively at 15, 30, 60 min interval compared to melatonin end placebo (~S0.05) (Figure 3). but there were no

!I! .i difference in the time needed for TDT score or dot

, , ,

i

Nnl w i t

All: -

26-SEP-2009 10:58 DEPT.OF ANAESTHESIA KKUH 4679364

4

T At. CWCTERISTYCS OF MELATONIN AND MIDAZOLAM

1 the sleep form stical lf the

due local >f the at 24 bown :allad >at of tiants their scbo cages

The nts in y '9t d d

POUP fenac

Trbla:l . Compwlron MNutnher of Pat tmt ,~ aar Prc cmd'~od Gerutivs atages in relation to VAS-umimty of thme h ~ ~ n n r p y

5 ) ~ p-value Vdablm Plaocbo Midazolam Malntnnis

pre-anx.c Nor 19 20 21 4.000 1

nnxinw Al~xiouo

Bxtramcly Anx.

'B Not

nnxioilw Anxiwn

Extremely Anx.

P ~ w - 3 0 Nnt

anxibun Anxious

extremely Anx.

.!!€Mu& Not

anxiour Anxiouli .

Extrcmoly Anx.

PaRt-anx.15 No1

mxioun Anxioun

I Saudi JW o f -ia, Vd. 1, No. I. April 2007

We have. demonstrated that patieutv who received ptemedication with either sublingual 0.5% midazolam (0.1 rng/Kg) or melatonin (0.05 rng/Kg) had significant decrease in anxiety levels .We also noted that there was significant increase in sedation level with midazolam versus melmnin prsoperatively. Previously r e studied the effect OF melatonin as pwmedication compared to midamlam in padents receiving general anaesthcsia17.

For a long period of time oral benzodiaxepine arc used as prernedicatiotr:t'or their anxiolytic effects in performing local blocks fnr cntaract surgeryta. Ophthalmologists are concorned becnuse of ita sedative and hangover effects. [t is documerilad in' other studies that pmmedication with midazolam was aaswidted with preoperative anxiolysis, sedation and impairmant of psychomotor skills'9s2" that combination effects were not good for a patient who underwent local block for ophthalmic surgery and in whom the ophthalmologist needs full cooperation of the patient while performing surgery.

In this study the dose of melatonin O.OSmg/Kg showed ao sedative effect compared with midazolamz1. When compared .in the preoperative period only patients in the midazolnm group experienced sign~ficant impairment of psychomotor skills and sipnifioont sedation compared to malatonin and control groups. There was signiticant reduction in the anxiety in the melatonin and midazolarn group when compared with control prciiperatively. However, there was no significai~t diflermce between all the groups regarding anxiety, sedation scores and TDT performance postopemtively. Amnesia was notable anty in the midazolsm gmup for one preoperative event. The amnesic proparties of benzodiazepinas are alroady well documentedz3. Our result8 showed that. melatonin had no nmncaic effects. 'L'he Tl7T deviation all~l score impainncnt tulutive to tile bweline wnr notcd in Ulc ni.iJwolnm .gtoup in the pxeopml:ive period and ~cdative eflccl w ~ 6 fit gadc 4 (?sleep not amliaable). Our rrsnlts are in acr.ordru1ce with the O~~IC'S ~ r t u d i ~ on pyychnmnrot f u ~ ~ c t ~ ~ m x produced by rnidazolnrn premcdication''~ ''. On the ocher hand, with melatonin the dose used in our study, there was no impairment in TDT sconn relative to baseline st peak effect time of 30.60 The peak sadatiun e€%cts of midazolam were notad at 30 and 60 min respectively after sublingual administrationa5, No patient was asleep in the tnalatonin group at all

26-SEP-2009 10:58 DEPT, OF ANAESTHESIA KKUH 4679364 P, 05

levels. The I.lbe of 'melatonin in anaesthmitl was "arted by the author ar a premedicstion drug and found to be pood when comp~md with the sublingual midazolam and even nnw onward mehonin i* bcing tried as intravenous induction agent in rats (1 7.26).

" group3

fb pvalue V h b l w PIacaho . Midazxym-- Melatonln

Awake 25 25 25 1 .O

J!lHau Awake 25 23 25 0.13 WRY I Asleep 1 1

PmnafW! AwakD 25 11 23 4.0001 h w n y B 2 Aslaap 3 Aaletp & not - 3

arousable

l3ssMQ Awake 25 11 24 <0.0001 Dmwny S 1 Asleep 6 Anlmp&no( - 3

lroU0~blt

Poat-asd-IS Awake 25 23 25 0.35 h w s y 1

I!Qmd& Awake 25 23 25 0.35

_ h w y 1

We wncluded that sublingual melatonin is better than sub l ingua l mida.mlnm for premedicrrtion of adult patients undergoing cataract s m g q under local ~ t l a e ~ t h a ~ i ~ . Ft~rtheirnore, unlikc benzo- diampinee. melatonin does not induce hangover eRkcts.

1985; 2271714-20, 3. hitar RI, Tan DX, Poa(tgoler B, Mcncndar.-Ptlncz A, Chen

LD, Saarola S. Molntosl~~ an n h a rarlic~l soavcnper: implicnlianu for aging and a~a-related d i s e ~ e e . Ann NY Acad Sa IY94,719:1-12.

4. Slankov B, Franchini F, Reitn. RJ: Melaionin binding sitan in the ccntrnl nmoua ftyntern. Bruin Rar Brdl~l Rav 1991; 16i245.56.

5. Cramar H. Rudolph J. Conwbmch V. Kmdsl K: On thh e w c c ~ of melatonin on rlwp and bahnviour in man. Adv Binohem hychophrrmaco 11974; I 1:187-91.

6. Wurtman HJ, ~ h d a n w n IV: ~mprowrnont of sleep quality by meistonin. Lancet 1995; 346: 1491-2.

7. Knlbe A. Kslas JD, Soharf MB, Ten TJ.: Hypnbticu and altered sleep-drpnm paltomu: all n i ~ h t EEG ntudiee of chlorsl hydrate, flumeyarn nnd methaqraln~io. Aroh Ctcn Paychiahy 1970; 23: 219-25.

8. Dement WC, Zmcone VP, Aadda~ E, Smvthc H, Carak.dnn M: SleOp laboratoty bnd clinical etudica with flurazapam, 'Ihe bonzodiaecpina~. Edited by Oarrnttini S, Munmnin E. Randall LO. New York, Rsvan Preaa, 1973, pp 599-61 1.

9. Fmderickuon PA, Kruopr BR! lnmmnia eabociatDd with ~ p a c ~ f i c polyaomnnpphia findings. principle^ and prncticc of albtp modicine. Edited by Krykbr MH, Rnth T, Demon! WC. Philadelphia, WE! Samdcrn, 1989, pp 484-5.

10. Zlidanova N, Wurtman Rf, Lynoh ?lJ, YVCR JR, Dollins AB, Morsbito C, Mstho~on 3K, Sthornor DL. Sltcp-inducing effeots of low doaen of malntcmin ingentad in the evcnlrlg. .. Clin Pharmacol Thcr 1995; 57552-8.

1 1. Petrie K, Conaglan JV, Thompwn 1. Chumhcrlain K. E h t '; of mcl~tonin on jet lng aRer long haul fliehrs. BMJ 1989; 298:705-9.

12. Anndt .I. Melatonin. Cli~i Bndoorinol 19Rli; 29: 205.29, 13. Dawson D. Encal N. Melatunin rmd ~ l w p in humnnn. .I

Pined RCR lV93; 15:l-12. 14. Karl HW. Rodmbcqor JL. h h MG, Ruffle JM;

Trannrnoca~l admlnirfmtion of mihmlrrn for pmcdication of pediatric paliantu. Cornparinon of tho nasal and uubl in~a l mute, Anestheeiology 1993; 7[1:885-91.

15. Kontinan VK, Mamuksela E-L, Snrirela J: Prumadication ,

with sublingual triazolam comparpd with ornl diatcpm. Can J Anassth 1993; 40: R2Y-34.

16. Aitkm RC: Manauremmt or fecling~ uninp viwal annloguc acalo. Pmo R SOC Mcd 1969; h2:919-43.

17. Nnguib M, Samarkandi AH, Premcdication melatoniit, a doublo-blind plaodba-controlled oomplviaon with rn!dazolm. Brit J Allaolltb 1999; 82(6):R75-RO.

18. Lang E, Schafer M, Bruninhnlz V. Midnzolam nu oral .. pren~sdicatiu~~ lor luau1 nnesthcaln. Anaeaihoai# 1987: 36(5);197-202.

19. Richarclnrm MC, =stop& LW, Andull& H. Midamlnm pmncdication inoreanes acdation hut doen not prolon~ i ,::. dieaharge ti- aflar hrinf mltpntint gemmi M C R ~ ~ G B ~ ~ for Iaprm~c~pic ubal ibriih.Lh. Annth Analg 1997; B5:M 1 - . . 5 .

20, Cihoncim MM. Block RI, Sum PST, El-Zahnby WM, Winrich8 N . The intaractions of mldlzcrlum and flumrzenil on hurmn memory and ~mpnition. Anesthesiol 1993; %i:

1. Weaver DR' Stshlc Jii, Stopa M. Repprrt AM. Melatonin 79: 1 183-92. 1 raOe~ton in h u m h~patknlamus pi him^: 21. Shafea A, white PF, . I l q ~ ~ h r m MI,, bozc VA. hnpal lmt $ hpliwlionw Tor oirwdlnn and WprfIA~mtivr mRponses ta

I pramedlcation: use of midaznlarn and opioid analgasic. molatonin. J Clin Endocrinol Metab 1993; 76:295-301. Anestheaial l PR9; 7 1 ;495-501.

2m TfUWUhn L- Uafid CJ, Almailln OF. M~laronin: a 22, Nagulb M, Samwkandi AH. comparative dot@*eponae ,? cmrAinrthrg oipnl for mammalinn mpmduotion?. Scicncc c R a t ~ of melatonin and t n i c l u n l ~ ~ for pomdbntion of i, .. .

Saudi JnnaaofAa&ahaia,Vol. 1.Nb. L,Apil2W7

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CHARACTERISTICS OF MELATONIN AND MIDAZOLAM 25

m tbe . Adv

r md jdd of I asn

ndult patients: s doubla blindad placebo-cantrolled study. 25. Lim TW, Thomas B. Choo SM. Premtdication with . Anesth Anal8 2000; 91(2):4'/3-9. midazblem irr mom offectivs br tha rublingual than on1

23. ohonaim MM, Mewnldt SP. Rnnnmrlisxsphs~ nnd humnn mula, Cw I Anaosth 1YY7; 44:7234. memory. A review. Aneathc~iol1990; 72;926-38. 26. Nquib M. Hnmmond DL, Bdar M, Cutkomp J , Qucl*l I..

24. L i a h a m HR, Waldhaueer P, O*rfia@ a, Lynoh HJ, Iudioulion of genal*l anasthe81a by molntnnin: Comparntive W w n n n RI. Effoots o f mehluuiu oa human mwcl find doso-effmt atudict with U~iupsntal and. pmpofol. pcti~manw. Brah Roe 1984: 323:tOl-7. Ancathcniol2W 1 ; 95:A!3 73.

azolam nolong =in for 35301-