the therapeutic effect of adding dextromethorphan to...

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Clinical StudyThe Therapeutic Effect of Adding Dextromethorphan toClonidine for Reducing Symptoms of Opioid Withdrawal:A Randomized Clinical Trial

Ayyoub Malek,1 Shahrokh Amiri,1,2 and Bohlool Habibi Asl3

! Clinical Psychiatry Research Center (CPRC), Tabriz University of Medical Sciences, Tabriz, Iran"Department of Psychiatry, Razi Psychiatric Hospital, El Goli Boulevard, P.O. Box #$#%, Tabriz, Iran&Department of Pharmacology, Tabriz University of Medical Sciences, Tabriz, Iran

Correspondence should be addressed to Shahrokh Amiri; [email protected]

Received (May !"#$; Accepted ## June !"#$

Academic Editors: W. El-Hage, V. Sar, T. Shibre, and H. P. Volz

Copyright © !"#$ Ayyoub Malek et al.)is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Dextromethorphan is a noncompetitive N-methyl D-aspartate receptor antagonist that is clinically feasible forrelieving the opioid withdrawal symptoms. )is study compares the e*cacy of a combination therapy with dextromethorphanand clonidine to treatment with clonidine alone. Methods and Materials. In this double-blind randomized clinical trial, patientswere selected from inpatients of detox and rehabilitation ward of Razi Hospital, Tabriz, Iran.)ey were randomly allocated to twogroups receiving either clonidine (".&–#.!mg/day) or clonidine and dextromethorphan ($""mg/day). Withdrawal symptoms wereevaluated in the +rst day of admission and again !&, &,, and -! hours later. Results.)irty male patients completed the trial in eachgroup. Withdrawal symptoms began to decrease in the second day in patients receiving dextromethorphan and clonidine whilepatients receiving clonidine experienced the more severe symptoms in -! hours. Analysis of variance of the symptom severity scorerevealed a signi+cant group ! time interaction (" = 14.25; # < 0.001), so that patients receiving dextromethorphan plus clonidinehadmilder symptoms during three days in all of themeasurements compared to clonidine group.Conclusion. Combination therapyof dextromethorphan and clonidine would result in milder opioid withdrawal symptoms compared to clonidine alone with areduction beginning at the second day.

1. Introduction

Addiction is one of the most disturbing and problematicsocial phenomena in current years with known social,economic, and individual detriments. Unfortunately thisproblem has been rising in Iran during the last two decades.Documented reports have shown that there are #!""""" to!"""""" substance abusers in Iran. Mokri et al. report thenumber to be &"""""" abusers in !""! [#]. )ese researchesdemonstrated that opium and heroin are themain substancesbeing abused while achieving a complete abstinence is themain expected outcome for treatment of addiction.

Detoxi+cation is the +rst step of substance abuse/dependence treatment and researches about brief and cost-e.ective methods receive a lot of interest in Iran [!]. Long-term opioid use would increase the cyclic Adenyl cyclasein noradrenergic system of the locus coeruleus. Hence this

compensatory increase in cyclic Adenyl cyclase would resultin adrenergic withdrawal symptoms during rapid opioidcessation.

Some pharmacological agents (opioid agonists, opioidagonist-antagonists, opioid antagonists, and alpha-! ago-nists) are studied and used in opioid detoxi+cation [!]. )ee*cacy of clonidine (as an alpha-! agonist) in controlling thewithdrawal symptoms is established in randomized placebo-controlled clinical trials [$]. A review study by Raith andHochhaus in !""& in Germany concludes that three mainmechanisms are responsible for opioid tolerance and thewithdrawal syndrome dependence which are upregulation ofAdenyl cyclase and nitric oxide synthetase and activation ofNMDA receptors. Consequently the use of alpha-! agonists(e.g., clonidine) and NMDA antagonists (e.g., dextromethor-phan, ketamine) may minimize the tolerance phenomenonand decrease the withdrawal symptoms [&].

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)e e*cacy of dextromethorphan is also approved byearlier studies. A randomized clinical trial by Koyuncuogluand Saydam in #((" compared the e*cacy of dextromethor-phan and diazepam to a combination of chlorpromazine anddiazepam on treating withdrawal symptoms of heroin. )eyshowed that those patients receiving dextromethorphan anddiazepam would experience milder withdrawal symptoms[%].

Considering the detoxi+cation phase as the +rst step ofthe treatment of opium-addicted patients and the di.erente.ect site of NMDA antagonists (e.g., dextromethorphan)and alpha-! adrenergic agonists (e.g., clonidine), we decidedto evaluate the synergistic e.ects of thesemedications in con-trol and relief from opiate withdrawal symptoms. Achievingsuccess in the +rst step of treatment might promise furtheraccomplishments.

2. Materials and Methods

)is study was performed as a double-blind randomizedclinical trial in Razi Hospital, Tabriz, Iran. Sixty patients,based on the results of the similar studies, were selectedfrom among inpatients of detox and rehabilitation ward.)einclusion criteria were male sex, age range of !" to &" years,positive morphine test, the diagnosis of opiate dependenceaccording to the DSM-IV-TR criteria, and mild cases ofwithdrawal syndrome in severity based on the Clinical Opi-ate Withdrawal Scale (COWS). )e inclusion criteria wereselected according to Gerra et al. who previously reportedthe interrelation of sex and the response to detoxi+cation [']as well as factors introduced by previous similar studies andstudies about the e.ective factors in successful detoxi+cation[-–(]. Also, due to medical ethics observations only mildcases of withdrawal syndrome were selected. To control thewithdrawal symptoms in severe cases it was possible thatwe change the treatment protocol and use di.erent dosingor add other drugs. Exclusion criteria included (#) psychoticpatients (!) severe somatic diseases including hepatic or renalinsu*ciencies (creatinine > #.!mg/dL, ALT > &" IU).

A/er giving a written informed consent, the selectedpatients, based on the inclusion and exclusion criteria, wererandomly allocated to two groups receiving either clonidinealone or a combination of clonidine and dextromethorphan.For blinding the study, the examining physician who ful+lledthe Clinical Opiate Withdrawal Scale (COWS) was di.eredfrom the physician who prescribed the drugs and also theprescribed drugs in one group were not clear for the patientsin the other group.

)e +rst group received clonidine ".&–#.!mg per dayin three divided doses according to the patient’s tolerance,Clonazepam #mg every eight hours, and acetaminophen%""mgevery six hours. Acetaminophenwas used as analgesicand Clonazepam was used as a sedative and anxiolytic agentaccording to the standard detoxi+cation protocols.

)e second group received clonidine ".&–#.!mg per dayin three divided doses according to the patient’s tolerance,Clonazepam #mg every eight hours, acetaminophen %""mgevery six hours, and dextromethorphan -%mg every sixhours.

Tolerance of patients for e.ects of clonidinewas evaluatedby their blood pressure while the systolic blood pressure lessthan ("mmHg was set as the threshold for dose modi+ca-tion. )e dextromethorphan formulation was prepared bypharmacists in Tabriz University of Medical Sciences. )eother medications were selected from available preparationsof the same company to obtain the same e.ects.

)e treatment duration was four days. All of the patientswere evaluated for severity of withdrawal symptoms at theadmission time and !&, &,, and -! hours later by a physicianblinded to the grouping of patients.

)e Clinical Opiate Withdrawal Scale (COWS) was usedby theAmericanAssociation ofAddictionMedicine as a goodindicator of clinical severity of withdrawal symptoms [#"].COWS estimates the severity of opioid withdrawal symptomsin ## categories: resting pulse rate, sweating, restlessness,pupil size, bone or joint aches, runny nose or tearing,gastrointestinal upset, tremor, yawning, anxiety or irritability,and goose0esh skin. )e total score is set as the indicator ofseverity of opioid withdrawal symptoms.)e symptoms maybe subdivided into four categories according to the total scoreas mild (%–#! scores), moderate (#$–!& scores), relativelysevere (!%–$' scores), or very severe (more than $' scores).

)e face validity of Persian version of COWS was eval-uated by some psychiatrists. As it was completed by twophysicians during the study, the interobserver reliability wasassessed in #, patients and the Pearson’s correlation testshowed positive signi+cant correlation between evaluators(# < 0.0001) with a Cronbach’s alpha being ".("- showinga high reliability.

)e study proposal was approved byMedical Ethics Com-mittee of Tabriz University ofMedical Sciences in accordancewith the principles of the Declaration of Helsinki. )is trialis registered with the Iranian Clinical Trials Registry (IRCT!"#!"-#('(-!N!).

)e data was analyzed by SPSS ver.#-. )e continuousdata are shown asmean± SD.)e principal statistical analysisevaluated the severity of thewithdrawal symptoms using a !!! repeated analysis of variance (ANOVA) design with a groupfactor (clonidine versus clonidine and dextromethorphan),and a repeated-measures factor (pretreatment; !&, &,, and -!hours a/er admission). # value less than "."% was consideredsigni+cant.

3. Results

)irty patients completed the trial in each group. No sig-ni+cant di.erences were observed between the two groupsregarding basic characteristics including withdrawal symp-toms at admission time. All were male and with Azeri ethnicbackground. )ese data are shown in Table #. )ere wereno clinically signi+cant adverse events in regard to the useddrugs’ side e.ects during the trial.

Analysis of variance of the symptom severity score (byCOWS) revealed a signi+cant group ! time interaction (" =#&.!%; # < 0.001), so that patients receiving dextromethor-phan plus clonidine had milder symptoms during threedays. As illustrated in Figure #, symptom severity in the

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T1234 #: Severity score of opiate withdrawal symptoms as mean ±SD.

Clonidinegroup

Clonidine andDextromethorphan

group# value

Number of patients $" $" —Initial symptomsscore 2.7 ± 1.9 3.4 ± 2.6 ".#-

Age 29.3 ± 3.5 28.9 ± 4.3 ".%'Systolic bloodpressure 125.2 ± 13.6 125.4 ± 12.5 ".'-

Diastolic bloodpressure 75.4 ± 10.1 74.9 ± 10.1 ".(,

two groups had a di.erent pattern and patients receivingdextromethorphan experienced milder symptoms in all ofthe measurements compared to clonidine group.

At Admission (Baseline).)e withdrawal symptoms weremild at baseline (total score from +ve to #! points). )ewithdrawal symptoms severity (mean total score) was alikebetween clonidine group (2.7 ± 1.9) and dextromethorphanand clonidine group (3.4 ± 2.6) with no signi+cant di.erence(# = 0.17).

A'er "$ Hours from Admission. In both groups the with-drawal symptoms were increased compared to the baseline.)is increasewasmore in clonidine groupbutwithout signi+-cant di.erence (# = 0.18) compared with dextromethorphanand clonidine group (6 ± 2.8 versus 5.1 ± 2.9).

A'er $( Hours from Admission. In both groups the with-drawal symptoms were increased compared to the baseline.)is increase was more in clonidine group with a signi+cantdi.erence (# = 0.0001) compared with dextromethorphanand clonidine group (8 ± 3 versus 5.3 ± 2.6).

A'er )"Hours fromAdmission.)e severity ofwithdrawalsymptoms was signi+cantly (# = 0.0001) more in cloni-dine group compared with dextromethorphan and clonidinegroup (9.8 ± 5.1 versus 5.1 ± 2.8).

)e used drugs in this study were those used as routineagents in di.erent diseases and had no side e.ects in useddoses.

4. Discussion

)is study shows that dextromethorphan added to clonidineregimen has a better e*cacy compared to clonidine alonein controlling the mild withdrawal symptoms in male opioidaddicts.

In the patients receiving clonidine alone the withdrawalsymptoms increased across the study and reached theirmost severity a/er -! hours from admission, while patientswho received dextromethorphan and clonidine experiencedmilder symptoms.)eir symptoms decreased a/er a peak in&, hours from admission.

)e alpha-! agonists such as clonidine may decrease thewithdrawal symptoms by controlling the excess activity ofthe adrenergic system [##]. Clonidine is being used in thetreatment of withdrawal syndrome since #(," [#!–#&] and a

Estim

ated

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al sy

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oms

1 2 3 4Time of measurement

2.00

4.00

6.00

8.00

10.00

A, clonidineB, clonidine and dextromethorphan

F56784 #: Severity of withdrawal symptoms in patients randomizedto receive clonidine or clonidine and dextromethorphan measuredat admission, !&, &,, and -! hours later.

majority of detoxi+cation regimens are using it [#%], but itse.ectiveness is not optimal when used alone.

N-methyl-D-Aspartate (NMDA) receptors of the glu-taminergic neurotransmitter system are an activator media-tor of the central nervous system (CNS) and exist in di.erentsites of CNS. Hyperstimulation of these receptors in eventssuch as strokes, head trauma, and convulsive attacks wouldresult in neuronal death while their decreased activity wouldresult in schizophrenic status [##].

Kukanich and Pabich (!""&) report that dextromethor-phan is a noncompetitive antagonist of NMDA receptors thatis used as an antitussive, adjuvant analgesic, alcohol, andopioid withdrawal symptom reducer [#']. It is also used inclinical trials combinedwithmorphine resulting an increasedanalgesic e.ect [##]. )e fact that NMDA antagonists mayrelieve some withdrawal symptoms is a sign of associationbetween glutaminergic and opioid neurotransmitter systems.NMDA-antagonists would reduce the e.ects of opioids with-drawal on basal forebrain and amygdale, but they do nota.ect the locus cerelous. Moreover it seems that NMDA-antagonists would result in a delay in developing toleranceto opioid.

Another support comes from the study by Zhu et al.(!""$) showing that the increased expression of C-fos geneis related to withdrawal intensity in mice neonates anddextromethorphan may reduce the related mRNA amountand is also e.ective in relief of withdrawal symptoms [#-].

)e role of NMDA-antagonists in opioid withdrawalrelief is also described for another medication from thisgroup, memantine, which decreased the symptoms of with-drawal in heroin-addict patients [#,].

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A single-blind study by Bisaga et al. (#((-) evaluated therole of dextromethorphan in relief of withdrawal symptoms.)ey used dextromethorphan (-%mg +ve times a day) andthe result con+rmed its e*cacy in decreasing the withdrawalsymptoms and craving. Authors suggested that itmay shortenthe detoxi+cation period compared to methadone [#(].)eseresults are con+rmed by the present double-blind study aswell. In a similar study (!""-), it was demonstrated thatmemantine solely is e.ective in the reduction of subjectivesymptoms of withdrawal syndrome and the authors recom-mended that memantine may be used as an adjuvant therapyin the reduction of withdrawal symptoms [!"].

Simultaneously there have been e.orts to increase thebioavailability of dextromethorphan as well. A group ofopioid dependence patients were treated with a combinationof dextromethorphan and quinidine, aiming to decrease themetabolism of dextromethorphan and dextrophan level(Quinidine inhibits the metabolism of dextromethorphan,leading to reduce of dextromethorphan metabolite, dextror-phan, levels) [!#]. Authors found that this combination wasine.ective in reducing the withdrawal symptoms comparedto placebo and most of the patients le/ the study in six daysdue to the severity of symptoms.

In the study by Bisaga et al. dextromethorphan resultedin the reduction of withdrawal symptoms in the fourth day,which is longer than our results (reduction began in secondday). )is may be explained by metabolic di.erences of thestudy sample.

)is study had some limitations. )e study sample con-sisted of patients who had decided to undertake detoxi+-cation treatment. )is may decrease generalization of theresults as they were highlymotivated and this could in0uencetheir subjective complaints in part. However the objectivesymptoms could still measure their symptoms to a goodextent. )e double blind setting increased the accuracy aswell. )is study could not include a placebo group like mostof the studies in this +eld.

5. Conclusion

Dextromethorphan, as a NMDA antagonist, is e.ective inthe relief of withdrawal symptoms. Hence it is very usefulin increasing the e*cacy of clonidine and reducing theneed for opioid agonists. Added dextromethorphan to cloni-dine resulted in symptom reduction as soon as the secondday of admission while patients experienced very few sidee.ects.

Conflict of Interests

)e authors declare that there is no con0ict of interests.

Acknowledgments

)e authors would like to thank all subjects participating inthis study.)is studywas supported by grants from the TabrizUniversity of Medical Sciences.

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