Background. Population/Intervention(s)/ Comparison/Outcome(s) (PICO) Treatment of psychostimulant dependence

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1 updated 2012 Treatment f psychstimulant dependence Q3: Are pharmactherapies safe and effective fr the treatment f psychstimulant dependence (maintenance r relapse preventin) in nn-specialized settings? Backgrund Methadne, buprenrphine and naltrexne are knwn t be effective in the treatment f piid dependence. Their efficacy was recently examined in the Guidelines fr the Psychscially Assisted Pharmaclgical Treatment f Opiid dependence (WHO, 2009) and they are nt examined further here. Recent Cchrane reviews shw n effect f antipsychtics, antiepileptic r antidepressants in the treatment f stimulant dependence, althugh there has been interest in the use f dexamphetamines, disulfiram and naltrexne. A recent review f disulfiram fund n effect f disulfiram (de Lima, 2002). As there are n recent reviews f the ther tw medicatins, each f which are reviewed here. There are n medicatins cnsidered feasible fr the treatment f cannabis dependence reviewed here. The issue f benzdiazepine prescribing fr benzdiazepine dependence has nt been examined as the issue f gradual vs rapid withdrawal is cvered in the sectin n withdrawal frm benzdiazepines. Ppulatin/Interventin(s)/ Cmparisn/Outcme(s) (PICO) Ppulatin: Interventins: stimulant dependence (amphetamines, methamphetamines and ccaine) naltrexne dexamphetamine Cmparisn: Outcmes: placeb r treatment as usual stimulant use 1

2 psychscial utcmes adverse effects List f the systematic reviews identified by the search prcess INCLUDED IN GRADE TABLES OR FOOTNOTES Naltrexne fr stimulant dependence: New review by : Huynh N, & Clark N (2009, unpublished). Dexamphetamine fr stimulant dependence: New review by De Windt Mears J & Clark N (2009, unpublished). Narrative descriptin f the studies that went int the analysis Dexamphetamine fr stimulant dependence (ccaine and amphetamines and methamphetamines) A pilt randmized cntrlled study (n=41) f dexamphetamine substitutin in cmparisn t the standard f care fr amphetamine dependence fund that bth interventins reduced street amphetamine use (Shearer et al, 2001). The standard f care treatment, r cunseling, was ffered t all participants. The nly grup difference bserved was that the dexamphetamine grup were significantly mre likely t attend the cunseling and receiving twice as many sessins as the cntrl grup wh where set t receive cunseling nly. N serius adverse events were reprted in the treatment grup. Anther pilt randmized duble blind placeb-cntrlled study (n=30) f dexamphetamine fr ccaine dependence fund that the prprtin f ccainepsitive urine samples detected in the dexamphetamine grup declined cmpared t n changes in the placeb cntrl grup, althugh the grup differences was nt significant (Shearer et al, 2003). Three adverse events were nted requiring hspitalizatin: psychtic symptms and the tw ther were nt related t study participatin. Grabwski et al, 2001 cmpleted a duble-blind randmized study (n=128) f dexamphetamine fr ccaine dependence, which fund that there were fewer ccaine-psitive urine screens than the placeb grup after 3 mnths. Six subjects stated medicatin side effects as reasns fr drpping ut. Meta-analysis was nt pssible due t differences in treatment utcmes reprted and lack f reprting f standard deviatins f cntinuus measures. 2

3 Naltrexne fr stimulant dependence Hersh et al, 1998 cnducted a randmized, duble-blind, placeb-cntrlled study f Naltrexne (50mg/day) in 64 participants with cmrbid ccaine and alchl dependence during 8 weeks. They reprted 17 participants achieved cmplete abstinence frm ccaine fr the entire 8-week treatment perid, with n between-grup difference (X2=2.7, 1df). Furthermre, 29 participants were abstinent fr at least 2 cntinuus weeks fllwing randmizatin, with n between-grup difference (X2=0.8, 1df). A duble-blind, placeb-cntrlled study f Naltrexne (50mg) in 85 ccaine-dependent participants during 12 weeks, by Schmitz et al, 2001, fund n significant effect f Naltrexne n time t first ccaine-psitive urine. Hwever, there is a significant three-way interactin (functin f time, therapy and medicatin) indicates less ccaine use ver time amng subjects receiving Naltrexne. Overall, 14% f participants (n=12) abstrained frm ccaine cntinuusly ver the 12 weeks. Jayaram-Lindstrm et al, 2008 cnducted a randmized, placeb-cntrlled study f Naltrexne (50mg/day) in 80 participants with amphetamine dependence during 12 weeks. The results shwed that the Naltrexne grup differed in cntinuus abstinence rates (Brestlw test, t=6.36, p<.05) in favr f Naltrexne treatment. GRADE tables Table 1 Authr(s): Clark N Date: Questin: Shuld Naltrexne vs Placeb be used fr stimulant dependence? Settings: Bibligraphy: Hersh D, van Kirk JR, Kranzler HR (1998). Naltrexne treatment f cmrbid alchl and ccaine use disrders. Psychpharmaclgy (Berlin), 139: Jayaram-Lindström N et al (2008). Naltrexne fr the treatment f amphetamine dependence: a randmized, placeb-cntrlled trial. American Jurnal f Psychiatry, 165: Schmitz JM et al (2001). Naltrexne and relapse preventin treatment fr ccaine-dependent patients. Addictive Behavirs, 26: Schmitz JM et al (2004). Treatment f ccaine-alchl dependence with naltrexne and relapse preventin therapy. American Jurnal f Addictin, 13: Summary f findings Quality assessment N f patients Effect N f Design Limitatins Incnsistency Indirectness Imprecisin Other Naltrexne Placeb Relative Abslute Quality Imprtance 3

4 studies cnsideratins (95% CI) Percentage f negative urine samples (ITT analysis) (fllw-up mean 12 weeks; Better indicated by higher values) 4 1,2 randmized very very serius 4 serius 3 indirectness 5 imprecisin 6 % days stimulants nt used (self-reprts) (fllw-up 8-12 weeks; Better indicated by higher values) 3 1,7 randmized very serius 8 incnsistency 4 serius 10 indirectness 9 Abstinence (fllw-up mean 12 weeks; either abstinence fr the duratin f the study r 3 weeks cntinuus abstinence during the study) 3 7 randmized very serius 3 incnsistency 11 Severe Adverse Effects (fllw-up 8 weeks; Risk rati) 1 12 randmized serius 13 incnsistency 14 indirectness imprecisin serius 16 indirectness 15 30/123 (24.4%) /31 (6.5%) 17/127 (13.4%) 11/33 (33.3%) RR 1.83 (1.06 t 3.15) RR 0.19 (0.05 t 0.8) MD higher (12.89 t higher) MD 5.95 higher (0.64 lwer t higher) 111 mre per 1000 (frm 8 mre t 288 mre) 270 fewer per 1000 (frm 67 fewer t 317 fewer) VERY VERY CRITICAL Mild AE (# patients) (fllw-up 8-12 weeks; Risk rati) 1 1,7,17 randmized very serius 8 incnsistency indirectness serius 18 Mild AE (Mean # weekly events) (fllw-up mean 12 weeks; Better indicated by lwer values) 2 1,19 randmized Psychscial functin very serius 20 incnsistency 4 serius 22 indirectness 21 14/40 (35%) 0/40 (0%) RR 29 (1.79 t ) mre per 1000 (frm 0 mre t 0 mre) MD 0.3 higher (0.34 lwer t 0.94 higher) VERY VERY 0 n evidence 0 fewer per 1000 (frm 0 fewer 0/0 (0%) 0/0 (0%) Nt estimable CRITICAL available t 0 fewer) 1 Calculated using RevMan. 2 Jayaram-Lindstrm et al, 2008; Schmitz et al, 2004; Pettinati 2008; Schmitz et al, Jayaram-Lindstrm et al, 2008 study had adequate randmizatin, drp uts with 14/40 (35%) in placeb grup and 11/40 (28%) in naltrexne grup, utcme assessment masked adequately. Schmitz et al, 2004 study did nt describe the randmizatin methd, verall 66% drp ut rate. 4 I squared = 89%. 5 Schmitz et al, ccaine/alchl dependence. Jayaram-Lindstrm et al, amphetamine dependence. 6 n= Hersh et al, 1998; Jayaram-Lindstrm et al; 2008; Pettinati Jayaram-Lindstrm et al, 2008 study had adequate randmizatin, drp uts with 14/40 (35%) in placeb grup and 11/40 (28%) in naltrexne grup, utcme assessment masked adequately. Hersh et al, 1998 study did nt describe randmizatin methd, 29/64 (39%) drp uts. 9 Jayaram-Lindstrm et al, amphetamine dependence. Hersh et al, ccaine/alchl dependence. 10 Naltrexne n=123 and placeb n= I squared 28%. 12 Hersh et al, Hersh et al, 1998 study 29/64 (39%) drp uts. 4

5 14 Only 1 study. 15 ccaine/alchl dependence. 16 n = 64 and upper cnfidence limit crsses a risk f Jayaram-Lindstrm et al, n=120 and estimate with a cnfidence interval that crsses Schmitz et al, 2001 and Schmitz et al, 2004 study did nt describe the randmizatin methd, verall 66% drp ut rate. Schmitz et al, 2001 study did nt describe the randmizatin methd, 43/85(51%) drp uts. 21 Schmitz et al, ccaine/alchl dependence. Schmitz et al, ccaine dependence. 22 n=165 and SMD with a cnfidence interval that crsses 0. References Grabwski J et al (2001). Dextramphetamine fr ccaine-dependence treatment: a duble-blind randmized clinical trial. Jurnal f Clinical Psychpharmaclgy, 21: Hersh D, van Kirk JR, Kranzler HR (1998). Naltrexne treatment f cmrbid alchl and ccaine use disrders. Psychpharmaclgy (Berlin), 139: Jayaram-Lindström N et al (2008). Naltrexne fr the treatment f amphetamine dependence: a randmized, placeb-cntrlled trial. American Jurnal f Psychiatry, 165: Pettinati HM et al (2008). A duble blind, placeb-cntrlled trial that cmbines disulfiram and naltrexne fr treating c-ccurring ccaine and alchl dependence. Addictive Behaviurs, 33: Schmitz JM et al (2001). Naltrexne and relapse preventin treatment fr ccaine-dependent patients. Addictive Behavirs, 26: Schmitz JM et al (2004). Treatment f ccaine-alchl dependence with naltrexne and relapse preventin therapy. American Jurnal f Addictin, 13: Shearer J et al (2001). Pilt randmized cntrlled study f dexamphetamine substitutin fr amphetamine dependence. Addictin, 96: Shearer J et al (2003). Pilt randmized duble blind placeb-cntrlled study f dexamphetamine fr ccaine dependence. Addictin, 98: WHO (2009). Guidelines fr the psychscially assisted pharmaclgical treatment f piid dependence. Geneva, Wrld Health Organizatin. 5

6 Frm evidence t recmmendatins Factr Narrative summary f the evidence base Explanatin One ut f the three studies (n=178) f dexamphetamine prescribing all fund a reductin in stimulant drug use in the treatment arms, althugh meta-analysis was nt pssible due t incmplete data reprting. Dexamphetamine prescribing did nt appear t be assciated with significant side effects cmpared t placeb. The 5 studies (n=372) examining naltrexne fr stimulant dependence shwed weak evidence f an effect f naltrexne cmpared t placeb in reducing stimulant use and severe adverse events (psychsis). The effect was nt cnsistent, being absent in tw f the studies, but theless statistically significant in meta-analysis. The results were the same fr ccaine dependent and amphetamine dependent patients, and were cmbined in the meta-analysis. In three f the studies participants were als alchl dependent. Summary f the quality f evidence Balance f benefits versus harms Lw t very lw. A small number f small studies with sme methdlgical flaws. In the absence f ther medicatin fr amphetamine and ccaine dependence, naltrexne culd have significant benefits. The risk f harm frm naltrexne in nn piid dependent patients is lw. An evidence fr dexamphetamine benefit was nt fund, althugh the reprts f adverse effects in the studies are nt higher than placeb, dexamphetamine as a medicatin is abusable and knwn t induce adverse effects. Define the values and preferences including any variability and human rights issues Dexamphetamine prescriptin may be viewed as cntinuing the dependence n stimulants, regardless f the health impact. 6

7 Define the csts and resurce use and any ther relevant feasibility issues Recmmendatin(s) Neither medicatin are particularly expensive, but availability is limited in sme cuntries. Naltrexne is nt a difficult medicatin t use in primary care settings. Dexamphetamines can be abused and s prescriptin f dexamphetamine raises a number f Dexamphetamine shuld nt be ffered fr the treatment f stimulant use disrders in nn-specialized settings. Strength f recmmendatin: STRONG Update f the literature search June 2012 In June 2012 the literature search fr this scping questin was updated. The fllwing systematic reviews were fund t be relevant withut changing the recmmendatin: Brackins T, Brahm NC, Kissack JC. Treatments fr Methamphetamine Abuse : A Literature Review fr the Clinician. Jurnal f Pharmacy Practice : 541 riginally published nline 17 Nvember 201.1DOI: / Castells X, Casas M, Vidal X, Bsch R, Rncer C, Rams-Quirga JA, Capella D. Efficacy f central nervus system stimulant treatment fr ccaine dependence: a systematic review and meta-analysis f randmized cntrlled clinical. Addictin 2007, 102, di: /j x Krupitsky EM, Blkhina EA. Lng-acting dept frmulatins f naltrexne fr herin dependence: a review. Current Opinin in Psychiatry 2010, 23: Lbmaier PP, Kune N, Gssp M, Waal H. Naltrexne Dept Frmulatins fr Opiid and Alchl Dependence: A Systematic Review. CNS Neurscience & Therapeutics (2011), 17, di: /j x 7

8 Mannelli P, Peindl KS, Wu LT. Pharmaclgical enhancement f naltrexne treatment fr piid dependence: a review. Subst Abuse Rehabil June ; 2011(2): di: /sar.s15853 Minzzi S, Amat L, Vecchi S, Davli M, Kirchmayer U, Verster A. Oral naltrexne maintenance treatment fr piid dependence. Cchrane Database f Systematic Reviews 2011, Issue 4. Art.N.: CD DOI: / CD pub4. (New search fr studies and cntent updated (n change t cnclusins), published in Issue 4, 2011.) Westver AN, Halm EA. D prescriptin stimulants increase the risk f adverse cardivascular events?: A systematic review. BMC Cardivascular Disrders 2012, 12:41 di: /