Keywords: Egypt, substance abuse, tramadol. Menoufia Med J 28: Faculty of Medicine, Menoufia University

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1 Originl rticle 591 An epidemiologicl study of trmdol HCl dependence in n outptient ddiction clinic t Heliopolis Psychitric Hospitl Nbil R. Mohmed, Lmi G. El Hmrwy, Amro S. Shlby, Mohmed S. El Bhy, Mohmmd M. Abd Allh b Deprtment of Neuropsychitry, Fculty of Medicine, Menoufi University, Menoufi, b Deprtment of Neuropsychitry, Nsser Institute, Ciro, Egypt Correspondence to Mohmmd Mostf Abd Allh, MBBCh, Deprtment of Neuropsychitry, Nsser Institute, 11 Abo Elhod Street, El Hdk, Fyoum Governorte, Egypt Tel: ; e-mil: psychitry1377@gmil.com Received 17 November 2014 Accepted 16 December 2014 Menoufi Medicl Journl 2015, 28: Objectives The im of this study ws to detect the prevlence of trmdol HCl dependency mong substnce busers, ssess the severity of ddiction, recognize comorbid psychitric disorders, nd identify risk fctors to strt trmdol buse. Bckground An incresingly lrming phenomenon of trmdol drug buse hs been demonstrted in the Egyptin community. Prticipnts nd methods The studied group hd 330 Egyptin substnce busers. They were subjected to the following: semistructured interview sheet, structured clinicl interview for DSM-IV (SCID-I) to dignose psychitric disorders, the ddiction severity index scle, nd urine screening for substnce buse. Results The prevlence of trmdol HCl dependency ccording to ll substnce busers ws 49%. The prevlence of comorbid psychitric disorders ws 43%. On studying risk fctors for trmdol buse we found sexul purpose nd plesurble effect were the strongest predictors. Conclusion The increse in the prevlence of trmdol HCl dependency over other substnces in the Egyptin community clls for more ttention from fmily nd eductionl nd helth institutes. Keywords: Egypt, substnce buse, trmdol Menoufi Med J 28: Fculty of Medicine, Menoufi University Introduction Trmdol HCl is centrlly cting synthetic opioid nlgesic used in the tretment of moderte to severe pin. It hs low ffinity to opioid receptors nd inhibits the reuptke of norepinephrine nd serotonin. Its nlgesic effect is prtilly blocked by nloxone [1]. Trmdol ws pproved for mrketing s sfe nlgesic in 1995.The mnufcturer initilly climed tht it produced only very wek nrcotic effects. Recent dt hve demonstrted tht its opioid ctivity is the overriding contributor to its phrmcologicl ctivity. The indequte product lbeling nd lck of n estblished buse potentil hve led to the sfety feeling of mny physicins to prescribe it to recovering nrcotic ddicts nd to be known s nrcotic busers. As consequence, numerous reports of buse nd dependence hve been received [2]. An incresingly lrming phenomenon of trmdol buse hs been hevily demonstrted in the Egyptin community in the lst 4 yers [3]. Although the issue of drug buse is not new to the Egyptin society, trmdol is ssocited with wide rnge of buse nd illegl trnsctions s it is esily ccessible nd redily provided t chep costs despite it being scheduled. The lleged usges of trmdol hve contributed considerbly to its populrity nd mssive use, especilly mong the youth nd middle-ged individuls s remedy for premture ejcultion nd for extended orgsm nd to increse sexul plesure [3]. It lso seems tht it is not only n Egyptin problem but lso hd been reported in Irn nd Isrel. Their low price nd vilbility without prescription mke them very populr. It relieve psychosomtic symptoms relted stress [4]. In the United Arb Emirtes, the phenomenon of selling trmdol in n unlwful mnner hs been on the rise. Twenty-one cses of trfficking trmdol hve been probed since Jnury 2010 [5]. Trmdol use is lrgely considered to be sfe by physicins. The most commonly reported side effects re dizziness, nuse, constiption, nd hedche Fculty of Medicine, Menoufi University DOI: /

2 592 Menoufi Medicl Journl However, trmdol toxicity my be underestimted; severl deths hve been reported when trmdol ws ingested lone in overdose [6]. The most common symptoms of cute trmdol overdose re centrl nervous system depression, nuse, vomiting, tchycrdi, nd seizures. Higher doses cn be ssocited with clssic opioid toxicity fetures of com, respirtory depression, nd crdiovsculr collpse [7]. Trmdol hs inhibitory ctions on the 5-HT2C receptor. Antgonism of 5-HT2C could be prtilly responsible for trmdol s reducing effect on depressive nd obsessive compulsive symptoms in ptients with pin nd comorbid neurologicl illnesses. 5-HT2C blockde my lso ccount for its lowering of the seizure threshold, s 5-HT2C knockout mice disply significntly incresed vulnerbility to epileptic seizures, sometimes resulting in spontneous deth. However, the reduction of the seizure threshold could be ttributed to trmdol s puttive inhibition of GABA-A receptors t high doses [8]. Higher doses of trmdol cn be ssocited with crdiovsculr collpse, com, nd respirtory depression. Ech of these fetures should be treted ccordingly, with no other specific tretment for seretonin nd norepineohrine reuptke inhinibitors (SSRI) toxicity [9].This study ims to detect the prevlence of trmdol HCl dependency mong substnce busers, ssess the severity of ddiction, recognize comorbid psychitric disorders, nd identify risk fctors to strt trmdol buse. Prticipnts nd methods Prticipnts This ws cross-sectionl study crried out over period of 12 months (from 1 November 2012 to the end of October 2013). The study group comprised of 330 Egyptins prticipnts. Their ge rnged between 12 nd 70 yers, nd both men nd women re included. They fulfilled the criteri for substnce buse ccording to DSM-IV-TR criteri. They were selected from the outptient ddiction clinic of Heliopolis Psychitric Hospitl. The protocol ws previously pproved by the Ethics Committee of this institution nd followed the tenets of the Declrtion of Helsinki. All of the ptients included in the study red the informed consent by themselves. evluted using semistructured interview sheet tht gthered generl dt nd drug hbits of the ptients (the type of drug, the route of dministrtion, the dose, etc.), structured clinicl interview for DSM-IV Axis I disorders (SCID-I), which ws used to dignose psychitric disorders, the ddiction severity index (ASI) scle, which provides multidimensionl ssessment for the problems presented by ptients with substnce buse disorders, nd urine screening for substnce buse. Sttisticl nlysis Dt were summrized s men nd SDs nd qulittive dt were summrized s numbers nd percentges. Comprison between two mens were mde using Student s t-test. The c 2 tble nd test were used for exhibition of dt. Menwhile, the binry logistic regression model with the enter method ws used for the clcultion of odds rtio nd 95% confidence intervl for trmdol misuse-relted risk fctors.the SPSS softwre, version (SPSS Inc., Chicgo, Illinois, USA), ws used for the sttisticl nlysis. Results The study ws conducted on 330 ptients who cme to the outptient ddiction clinic of Heliopolis Psychitric Hospitl. The study ws conducted s shown previously in the Prticipnts nd methods section. Figure 1 shows the prevlence of substnce bused in the studied group. About 43.94% (n = 145) of the ptients used polysubstnces, wheres ptients who used one substnce were s follows: trmdol 30.30% (n = 100), heroin 11.52% (n = 38), sedtives nd hypnotics 4.24% (n = 14), lcohol 3.64% (n = 12), cnnbinoids 3.03% (n = 10), nlbuphine 1.82% (n = 6), nd cocine 1.52 (n = 5). Figure 1 Mesurements nd questionnire After obtining orl consent from ech prticipnt, the study ws developed ccording to the stndrd in qulity improvement system in the ministry of helth nd popultion in Egypt. Prticipnts were The prevlence of substnces buse in the studied group ccording urine screening for drugs.

3 Epidemiologicl study of trmdol HCl dependence Mohmed et l. 593 Tble 1 shows the prevlence of ech drug within polysubstnce users. When nlyzing the frequency of ech drug mong polysubstnce ddicts, we found tht the prevlence of cnnbis within the group ws 83.4% (n = 121), the prevlence of trmdol within this group ws 43.45% (n = 63), the prevlence of heroin ws 46.9% (n = 68), the prevlence of sedtives nd hypnotics ws 48.97% (n = 71), nd the prevlence of lcohol ws (n = 28). Figure 2 shows the prevlence of ll substnce bused, with nlysis of polysubstnces. When nlyzing the frequency of ech drug within the whole smple (polysubstnce nd one substnce), we found tht the prevlence of trmdol ws 49%. This ws followed by cnnbinoids 40%, heroin 32%, sedtives nd hypnotics 25%, lcohol 12%, nlbuphine 0.18%, nd cocine Tble 2 shows the sociodemogrphic chrcteristics of trmdol-dependent ptients. It ws found tht the min ge of onset of strting trmdol buse ws ± yers: 80% of our smple ws mle nd 20% ws femle; 23% hd positive fmily history of psychitric disorders nd 25% hd positive fmily history of substnce buse. Figure 3 shows tht 41% hd comorbid psychitric disorders s follows: 9% suffered from schizophrenic nd other psychotic disorders, 6% hd nxiety disorders, 4% hd obsessive compulsive disorders (OCD) nd relted disorders,12% hd depressive disorders, 1% hd bipolr nd relted disorders, 4% hd somtic Figure 2 Anlysis of ll substnce bused by urine screening for ll drugs. symptoms nd relted disorders, nd 7% suffered from other diseses (3% feeding nd eting disorders, 2% sleep wke disorders, nd 2% sexul dysfunctions). Figure 4 shows tht the severity of trmdol dependence ccording to the ASI scle ws s follows: The psychitric dimension ws the most considerble problem in the studied individuls, followed by the fmily history dimension, the socil dimension, the occuptionl dimension, nd the legl dimension. The drug nd lcohol dimension nd the medicl sttus were the lest considerble problems mong the vrious dimensions of the ASI scle. Tble 1 The prevlence of ech drug mong polysubstnce users Drugs Frequency Percentge Trmdol Heroin Sedtive nd hypnotics Alcohol Cnnbinoids Sedtives nd hypnotics include benzodizepines, nonbenzodizepine hypnotics, nd some types of muscle relxnts. Tble 2 Sociodemogrphic chrcteristic dt of trmdoldependent ptients Sociodemogrphic dt Studied group (n = 100) [n (%)] Sex Mle 80 (80) Femle 20 (20) Age (yers) Men ± SD ± Rnge Age of onset (yers) Men ± SD ± Rnge Eduction level Not educted 15 (15) Primry 27 (27) Secondry 25 (25) University 33 (33) Residence Rurl 28 (28) Urbn 72 (72) Mritl sttus Single 53 (53) Mrried 36 (36) Divorced 5 (5) Widow 6 (6) Socil clss I High 28 (28) II Middle 48 (48) III Low 26 (26) Fmily history of Substnce buse 25 (25) Psychitric disorders 23 (23) The socioeconomic level ws ssessed ccording to the criteri determined by DHS-Egypt, 2005.

4 594 Menoufi Medicl Journl Figure 3 Figure 4 Comorbid psychitric disorders mong trmdol-dependent ptients. The severity of trmdol dependence ccording to the ddiction severity index (ASI). Tble 3 shows the risk fctors to strt trmdol buse s follows: 20% of the ptients strted trmdol buse for its plesurble effect (to improve mood), 19% of the ptients for sexul purpose (prolongtion of the time of intercourse), 13% to get more power for hrd work (to dely the senstion of ftigbility), 13% for pin relief, 11% s self-mediction to relieve depression, 10% s self-mediction to relive nxiety, 9% due to peer pressure, nd 5% for other purposes. Tble 4 shows the reltionship between the trmdol dose nd the occurrence of seizures; it ws found tht ptients who suffer from seizures s compliction were on significntly higher dose thn those who did not develop seizures. Discussion In the present study, opioids were the substnce of mjor problem in 43.73% of the substnce busers (trmdol tblets were the substnce of mjor problem in 30.30% of the prticipnts, heroin in 11.72%, nd nlbuphine in 1.82%). The present study re consistent with those of Htt [10], who found tht 61.9% of their prticipnts used opites, 18.5% used cnnbis, 15.8% used sedtives, nd 3.9% used lcohol; results of the study of Mohmed et l. [11] showed tht opioids were the substnce of mjor problem (in 30% of their prticipnts), especilly trmdol tblets. Concerning the sex, 80% were mles nd 20% were femles. The finding rises the following questions: the low number of women in the smple becuse of the low percentge of drug intke in women or becuse of the difficulty nd the lck of vilbility of tretment options for women? or becuse of shme nd stigm womn Tble 3 Risk fctors to strt trmdol buse Cuse of the strt Frequency Percentge Plesurble effect (improve mood) Sexul purpose (for prolongtion of the time of intercourse) Hrd work (to dely the senstion of ftigbility) For pin relief Self-mediction for depression Self-mediction for nxiety Peer pressure Others Totl Other cuses to strt trmdol buse: curiosity (3), for the tretment of insomni (1), nd for weight loss (1). would encounter if she joins substnce dependence tretment progrm? The prevlence of mle ptients over femle ptients in this study is consistent with the WHO globl survey [12], which supports the finding tht the estimted ttributble burden due to illicit use of drugs is 0.8% mong men nd 2% mong women. The study shows tht 53% of the ptients were single, 36% were mrried, 5% divorced, nd 6% widowed. Our results were consistent with Abdel-Mohsen et l. [13], who found tht 21.1% of the ptients were mrried, 64.9% were single, nd 14% were seprted. Fortythree percent of the prticipnts in our study were from the middle socioeconomic level, 28% were from the high socioeconomic level, nd 24% were from the low socioeconomic level. This result is consistent with Abulmgd et l. [14], who found tht 60% of the opioid users were from the middle socioeconomic level, 27% were from the

5 Epidemiologicl study of trmdol HCl dependence Mohmed et l. 595 Tble 4 The reltionship between the trmdol dose nd the occurrence of seizures Seizures Positive Negtive P vlue Test used Significnce Men SD Men SD As compliction 7.5 tblet Independent t-test Significnt* As withdrwl symptom 5.0 tblet Independent t-test Not significnt *Sttisticlly significnt (P < 0.05); Trmdol tblet equls to 225 mg of trmdol HCl. high socioeconomic level, nd12.5% were from the high socioeconomic level. Twenty-five percent of our smple hd positive fmily history of substnce buse; this results re consistent with those of Oksh [15], who reported tht more thn one-third of the users fthers nd lmost hlf of their reltives were substnce busers, nd this indictes the effect of exposure to drug-relted stimuli nd the distorted models of fthers nd reltives; we lso detected the significnt role of identifiction nd lerning in entering the dilemm of substnce buse. The ge of onset of drug buse ws 26 yers. This ws consistent with the studies of Hfeiz [16], who found tht in 83% of the ptients, the ge of onset ws in the rnge of yers, which cn be explined by the fct tht most substnce users re lso within this ge rnge. Forty-one percent of our smple suffered from comorbid psychitric disorders (SCID-I).We cn explin this by the fct tht in some cses, substnce is used s self-mediction tht helps in the resolution of the symptoms together with the rewrding effect of the substnce. This is consisted with Mohsen et l., tht found higher percentge of the co-morbid group use trmdol more thn the co-morbid group, which use sedtive hypnotic nd cnnbis. It is lso consistent with mny studies tht found tht chronic drug intke, especilly opites, is ssocited with brod rnge of psychitric mnifesttions rnging from intensely dysphoric withdrwl symptoms, depression, impulse control symptoms, intense nxiety, psychotic symptoms, especilly prnoid delusions nd hllucintions, nd suicidl nd self-injurious behvior. These psychitric disorders occur in ddition to tolernce, withdrwl, nd intoxiction symptoms of the different types of drugs [18]. Kieffer nd Evns [19] reported tht psychitric mnifesttions co-occurring with substnce dependence were interpreted s the long-term consequences of neurobiologicl dpttions nd the opioid system dysregultion to prolonged drug use. These phenomen re consequence of sustined m receptor stimultion by opite drugs inducing neurochemicl dpttions in opioid receptor-bering neurons. The results extend well beyond the rewrd circuits to other brin res, notbly those involved in lerning nd stress responses. Importnt regions re the mygdl, the hippocmpus, nd the cerebrl cortex, which re ll connected to the nucleus ccumbens. The severity of trmdol dependence ccording to the ASI scle ws s follows: the psychitric dimension ws the most considerble problem in the studied individuls, followed by the fmily history dimension, the socil dimension, the occuptionl dimension, nd the legl dimension. The drug nd lcohol dimension nd the medicl sttus were the lest considerble problems mong the vrious dimensions of the ASI scle. This is greement with the study by Strkowski et l. [20], who found tht psychitric ptients who use substnces hd more severe symptoms due to higher rtes of hospitliztion, lower rtes of remission during hospitliztion, more experience of mixed episodes, rpid mood cycling, nd persistent mood symptoms with tretment nd residul symptoms during recovery. The fmily nd socil dimensions of ddiction severity index (ASI) were consistent with Mohsen et l. [17], who found tht 1% of their prticipnts hd mild fmily problems, 38% hd moderte problems, 23% hd severe problems, wheres 36% hd extreme problems. It cn be explined by the ttribution of the genetic fctor [21], which is lso consistent with review on substnce dependence consequences, which sttes tht substnce use nd dependence is more thn helth problem; it is formidble morl, socil, nd economic chllenge with pndemic dimensions [21]. It ws found tht some ptients who were dependent on trmdol suffered from seizures s compliction. We found significnt reltion between the trmdol dose nd the occurrence of seizures. Ptients who developed seizures were on significntly higher dose thn those who did not develop seizures. The dose ws found to be of no significnce with regrd to developing seizures s withdrwl symptom. Ogt et l. [8] explined the reduction of the seizure threshold by high doses of trmdol due to the inhibition of GABA-A receptors. Shdin et l. [22] lso reported tht excessive dosge of trmdol leds to the development of seizures. Conclusion Trmdol HCl dependency is t the top of ll substnces bused in Egypt, t 49%, followed by polysubstnces t 43%.The prevlence of trmdol HCl dependency in men is more frequent thn in women. Trmdol HCl dependency is more prevlent mong young people thn in the older ge group. The most common

6 596 Menoufi Medicl Journl reson for trmdol HCL buse is to hve good time (plesure effect), to hve good sexul reltion (prolong the time of the intercourse), to increse the bility to work hrd (dely the senstion of ftigbility), peer pressure, nd to relieve emotionl distress in the form of nxiety nd depression. The Egyptin community needs more ttention from fmily nd eductionl nd helth institutes for the prevention nd the tretment of trmdol buse. Acknowledgements Conflicts of interest None declred. References 1 Dyer P, Desmeules J, Collrt L. Phrmcology of trmdol. Drugs 1997; 53 :Suppl 2: Clrot F, Goulle JP, Vz E, Proust B. Ftl overdoses of trmdol: is benzodizepine risk fctor of lethlity?. Forensic Sci Int 2003; 134: Slem EA, Wilson SK, Bissd NK, Delk JR, Hellstrom WJ, Cleves MA. Trmdol HCL hs promise in on-demnd use to tret premture ejcultion. J Sex Med 2008; 5: IRIN Middle Est, ISRAEL-OPT. Drug buse on the rise in Gz specilist s humnitrin news nd nlysis. A service of the UN Office for the Coordintion of Humnitrin Affirs. 5 Crckdown on Trmdol buse in the UAE An ISET Helthcre portl for mediclprofessionls in the MiddleEst. GurdinDte: 15 December Ripple MG, Pestner JP, Levine BS, Smilek JE. Lethl combintion of trmdol nd multiple drugs ffecting serotonin. Am J Forensic Med Pthol 2000; 21: Pothiwl S, Ponmplm R. Trmdol overdose. A cse report. Proc Singpore Helthcre 2011; 20: Ogt J, Minmi K, Uezono Y, Okmoto T, Shirishi M, Shigemtsu A, Uet Y. The inhibitory effects of trmdol on 5-hydroxytryptmine type 2C receptors expressed in Xenopus oocytes. Anesth Anlg 2004; 98: Chndrsekrn D, De Silv P, Dhtriy K. An uncommon presenttion of common drug overdose the dngers of underestimting trmdol. J Med Sci Res 2007; 1: Htt AH. Dul dignosis in substnce use disorders. An Egyptin study MD thesis. Egypt: Fculty of Medicine, Ain Shms University; Mohmed NR, Hmmd SA, El Hmrwy LG, Rjb AZ, El Bhy MS, Soltn MR. Dul dignosis nd psychosocil correltes in substnce buse in Menoufi. Egypt Menoufi Med J 2013; 26: WHO. Neuroscience of psychoctive substnce use & dependence. Genev: WHO; Abdel- Mohsen MY, Abdel Gwd TM, Khlil ME, Enb DA. Rediness to chnge of motivtion in substnce buse ptients MD thesis. Egypt: Psychitry Deprtment, Ciro University; Abolmgd S, Nsr AA, Erfn S, Mmdouh R, EL-Lwendi M. A group of Egyptin ddicts: users view for ddiction cuses nd its impct on self nd fmily. Egypt J Psychitry 2004; 23: Oksh A. Long term strtegy of ddressing nrcotics n Arb Egyptin perspective. Ammn: Royl College of Psychitrists in Jordn; Hfeiz HB. Socio-demogrphic correltes nd pttern of drug buse in Estern Sudi Arbi. Drug Alcohol Depend 1995; 38: Mohsen MY, Abdel Gwd TS, Hlim Z, Hnn AW. Psychitric comorbidity nd the severity of psychoctive substnce dependence, Egypt. J Psychitr 2004; 24: WHO. Neuroscience of psychoctive substnce use & dependence. Genev: WHO; Kieffer BL, Evns CJ. Opioid tolernce-in serch of the holy gril. Cell 2002; 108: Strkowski SM, Sx KW, McElroy SL, Kech PE, Hwkins JM, West SA. Course of psychitric nd substnce buse syndromes co-occurring with bipolr disorder following first psychitric hospitliztion. J Clin Psych 1998b; 59: Kertesz SG, Lrson MJ, Cheng DM, Tucker JA, Winter M, Mullins A, et l. Need nd non-need fctors ssocited with ddiction tretment utiliztion in cohort of homeless nd housed urbn poor. Med Cre 2006; 44: Shdni S, Brent J, Mousvi-Ftemi K, et l. Recurrent Seizures in Trmdol Intoxiction: Implictions for Therpy Bsed on 100 Ptients. Bsic Clin Phrmcol Toxicol, 2004; 111: