Table 2.
Summary of the Evidence on Pharmacotherapies for Cocaine Use Disorder, Stratified by Drug Class
| Outcomes | N studies per outcome; ROB (N = combined participants) | Summary of findings by outcome | Strength of evidence* | Comments and rationale for strength of evidence rating |
|---|---|---|---|---|
| Psychopharmacotherapies (antidepressants, antipsychotics, anxiolytics, cognitive enhancing drugs, and psychostimulants) | ||||
| Antidepressants (all) | ||||
| Abstinence |
1 SR of 8 RCTs17 (N = 942) 1 low-ROB RCT18 (N = 130) |
No difference. Meta-analysis of 10 RCTs, N = 1226, RR 1.27 (95% CI 0.99 to 1.63) |
Moderate | Inconsistent findings. Trend toward benefit disappeared when restricted to studies using strict criteria for cocaine dependence. |
| Use |
1 SR of 4 RCTs17 (N = 251) 1 low-ROB RCT18 (N = 130) 1 high-ROB RCT19 (N = 24) |
No difference. 1 SR reported a combined use of cocaine (self-reported or objective) RR of 1.05 (95% CI 0.91 to 1.21). Similar findings were reported in both more recent low-ROB and high-ROB RCTs. | Moderate | Indirectness (of outcome) |
| Lapse | 2 low-ROB RCTs20, 21 (N = 116) | Favors antidepressants. Participants abstinent at baseline with 1 cocaine positive UDS, combined RR 0.79 (95% CI 0.62 to 1.00). | Low |
Small body of evidence Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Lapse is defined as the first cocaine positive or missing UDS; relapse is 2 consecutive cocaine positive or missing UDS′. |
| Relapse | Favors antidepressants. Participants abstinent at baseline with 2 consecutive cocaine positive UDS′, combined RR 0.74 (95% CI 0.57 to 0.96). | Low | ||
| Retention |
1 SR of 27 RCTs17 (N = 2417) |
No difference. Meta-analysis of 33 RCTs N = 2918, RR 0.95 (95% CI 0.87 to 1.03) | High | Findings were similar in analyses limited to RCTs specifying DSM cocaine dependence criteria for inclusion. |
| Harms |
1 SR of 13 RCTs17 (N = 1396) 1 low-ROB RCT18 (N = 130) 1 high-ROB RCT19 (N = 24) |
No difference. 1 SR reported a combined withdrawal due to an adverse event RR of 1.39 (95% CI 0.91 to 2.12). Two more recent RCTs (1 low-ROB, 1 high-ROB) reported consistent findings. No difference. Two RCTs found no difference in severe adverse events by group. |
Withdrawal due to AEs: Moderate Severe AEs: low |
Treatment withdrawal findings are from 1 low and 1 high RCT and a SR/meta-analysis of 37 RCTs. The SR included studies with any definition of cocaine dependence or abuse. Findings of SAEs are from a small body of evidence. |
| Antidepressants (tricyclics) | ||||
| Abstinence | 1 SR of 5 RCTs17 (N = 367) | No difference. 3+ week abstinence, combined RR 1.55 (95% CI 1.10 to 2.17). Limited to DSM criteria for cocaine dependence (3 studies, N = 234): combined RR 1.41, (95% CI 0.93 to 2.14). | Low | 4/5 studies are of desipramine. |
| Use | 1 SR of 2 RCTs17 (N = 37) | No difference. Use of cocaine (self-reported or objective), combined RR 0.85 (95% CI 0.34 to 2.11) | Insufficient | Small body of evidence. Imprecise estimate. Indirectness (of outcome) |
| Retention | 1 SR of 15 RCTs17 (N = 1141) | No difference. Number of participants who did not complete the trial, combined RR 1.00 (95% CI 0.85 to 1.18) | High | Findings were similar in an analysis limited to RCTs specifying DSM cocaine dependence criteria for inclusion and in an analysis excluding high-ROB trials. 13/15 studies are of desipramine. |
| Harms | 1 SR of 5 RCTs17 (N = 381) |
No difference. Withdrawal due to an adverse event, combined RR 1.24 (95% CI 0.64 to 2.43) SAE: NA |
Moderate No evidence: SAE |
Findings were similar in analyses limited to RCTs specifying DSM cocaine dependence criteria for inclusion. Imprecise estimate. 4/5 studies are of desipramine. |
| Antidepressants (SSRIs): fluoxetine and sertraline | ||||
| Abstinence | NA | NA | No evidence | NA |
| Use | NA | NA | No evidence | NA |
| Relapse | 2 low-ROB RCTs20, 21 (N = 133) | Favors sertraline. Participants abstinent at baseline with 2 consecutive cocaine positive UDS′, combined RR 0.74 (95% CI 0.57 to 0.96). | Low |
Small body of evidence Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Lapse is defined as the first cocaine positive UDS, relapse is 2 consecutive cocaine positive UDS’. |
| Lapse | Favors sertraline. Abstinent at baseline participants with 1 cocaine positive UDS, combined RR 0.79 (95% CI 0.62 to 1.00). | Low | ||
| Retention |
1 SR of 7 RCTs17 (N = 527) |
No difference. The SR’s combined RR for participants not completing the trial was 0.99 (95% CI 0.70 to 1.71). No difference in 2 more recent RCTs. | Moderate | Inconsistent results. Findings favored placebo when excluding 1 outlier, and no difference was found when further excluding 1 high-ROB RCT. Indirectness (of population)—2 more recent RCTs enrolled only patients who had achieved abstinence. |
| Harms | 1 SR of 3 RCTs17 (N = 251) |
Favors placebo. Withdrawal due to an adverse event, combined RR 3.55 (95% CI 1.11 to 11.34). SAE: NA |
Low No evidence: SAE |
Imprecise estimate, small body of evidence |
| Antidepressant (SNRI): venlafaxine | ||||
| Abstinence | 1 low-ROB RCT18 (N = 130) | No difference. 1 RCT found no difference in 3+ week abstinence between groups (P = 0.94). | Insufficient | 1 single site study. |
| Use | No difference. 1 RCT found no difference in negative UDS′ between groups (P = 0.74). | Insufficient | ||
| Retention | No difference. 1 RCT found no difference in retention between groups. | Insufficient | ||
| Harms |
No difference. 1 RCT found no difference in withdrawals due to adverse events by group. No difference. 1 RCT found no difference in severe AEs between groups. |
Insufficient | ||
| Antidepressant (Atypical): mirtazapine | ||||
| Abstinence | NA | NA | No evidence | NA |
| Use | 1 high-ROB RCT19 (N = 24) | No difference. 1 RCT found no difference in study period use between groups. | Insufficient | 1 very small underpowered study. Details regarding randomization and allocation concealment NR. |
| Retention | NA | NA | No evidence | NA |
| Harms | 1 high-ROB RCT19 (N = 24) |
No difference. 1 RCT found no difference in withdrawals due to AEs between groups (none). No difference. 1 RCT found no difference in severe AEs between groups (because there were none). |
Insufficient | 1 very small underpowered study. Details regarding randomization and allocation concealment NR. |
| Antidepressant (aminoketone): bupropion | ||||
| Abstinence | 1 SR of 2 RCTs7 (N = 176) | Favors bupropion. 1 SR reported a combined 3+ week abstinence RR of 1.63 (95% CI 1.02 to 2.59). | Low |
Small body of evidence Imprecise estimates |
| Use | No difference. Use of cocaine, combined SMD 0.24 (95% CI − 0.06 to 0.54). | Low | ||
| Retention | 1 SR of 3 RCTs17 (N = 325) | No difference. The SR’s combined RR for participants not completing the trial was 0.99 (95% CI 0.79 to 1.25). | Moderate | Inconsistent results |
| Harms | 1 SR of 1 RCT7 |
No difference. Mean withdrawals due to AEs RD 0.00 (95% CI − 0.05 to. 0.05) SAE: NA |
Insufficient No evidence: SAE |
Small body of evidence |
| Antipsychotics (all) | ||||
| Abstinence | 1 SR of 3 RCTs8 (N = 139) | No difference. 1 SR reported a combined 3+ week abstinence RR of 1.30 (95% CI 0.73 to 2.32). | Low |
Small body of evidence Imprecise estimate |
| Use |
1 SR of 2 RCTs8 (N = 150) 1 high-ROB RCT22 (N = 18 opioid randomized, 41 enrolled opioid-dependent participants) |
No difference. | Low |
Small body of evidence Methodological limitations of studies. Indirectness of population. |
| Relapse | 1 high-ROB RCT22 (N = 18 opioid randomized, 41 enrolled opioid-dependent participants) | No difference. | Insufficient | Small, methodologically limited single trial. Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Lapse is defined as the first cocaine positive UDS, relapse is 2 consecutive cocaine positive UDS′. |
| Lapse | No difference. | Insufficient | ||
| Retention |
1 SR of 8 RCTs8 (N = 397) 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) |
Favors any antipsychotic. 1 SR reported dropouts RR 0.75 (95% CI 0.57 to 0.97). 1 high-ROB RCT of comorbid cocaine and opioid-dependent methadone-maintained participants found no difference in retention between groups. |
Moderate | Newer trial found no difference (indirectness of population). |
| Harms | 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) |
Withdrawals: no difference. SAE: NA |
Insufficient No evidence: SAE |
Small, methodologically limited single trial. Indirectness (of population) |
| Antipsychotics (first generation): haloperidol | ||||
| Abstinence | NA | NA | No evidence | NA |
| Use | NA | NA | No evidence | NA |
| Retention | 1 SR of 1 RCT8 (N = 31) | No difference. 1 SR reported a RR for participants not completing the trial of 1.50 (95% CI 0.63 to 3.57). 1 head to head trial found no difference between haloperidol and olanzapine (N = 31; RR 1.50, 95% CI 0.63 to 3.57). | Insufficient | Findings are from a single study in a SR/meta-analysis of 14 RCTs. |
| Harms | NA | NA | No evidence | NA |
| Antipsychotics (second generation): aripiprazole, olanzapine, risperidone, quetiapine | ||||
| Abstinence | 1 SR of 3 RCTs8 (N = 139) | No difference. Three studies in a SR found no difference between an atypical antipsychotic and placebo on sustained abstinence. | Low |
Small body of evidence Imprecise estimate |
| Use |
1 SR of 1 RCT8 (N = 31) 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) |
No difference. 1 RCT from 1 SR and 1 high-ROB RCT of opioid-dependent participants found no difference between groups. | Insufficient |
Small body of evidence Methodological limitations of studies. Indirectness of population. |
| Relapse | 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) | No difference. 1 high-ROB found no difference in relapse by group. | Insufficient | Small, methodologically limited single trial. Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Lapse is defined as the first cocaine positive UDS, relapse is 2 consecutive cocaine positive UDS′. |
| Lapse | No difference. 1 high-ROB found no difference in lapse by group. | Insufficient | ||
| Retention |
1 SR of 7 RCT8 (N = 365) 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) |
No difference. Seven studies in 1 SR and 1 high-ROB RCT of comorbid cocaine and opioid-dependent methadone-maintained participants found no benefit of atypical antipsychotics on study retention | Moderate | Newer trial found no difference (indirectness of population). |
| Harms | 1 high-ROB RCT22 (N = 18 randomized, 41 enrolled opioid-dependent participants) | No difference. 1 high-ROB RCT of comorbid cocaine and opioid-dependent methadone-maintained participants found no difference in withdrawals due to AEs by group. SAE: NA |
Insufficient No evidence: SAE |
Small, methodologically limited single trial. Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). |
| Antipsychotics (other): reserpine | ||||
| Abstinence | NA | NA | No evidence | NA |
| Use | 1 SR of 1 RCT8 (N = 119) | No difference. 1 study in the SR found a no difference in use between groups. | Insufficient | Small body of evidence. Imprecise estimate. |
| Retention | NA | NA | No evidence | NA |
| Harms | NA | NA | No evidence | NA |
| Anxiolytics: buspirone | ||||
| Abstinence | 1 High-ROB RCT26 (N = 62) | No difference. 1 RCT found no difference between groups in the mean number of days of (post-discharge) abstinence. | Insufficient | Small, methodologically limited single trial. Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Lapse is defined as the first cocaine positive UDS, relapse is 2 consecutive cocaine positive UDS′. |
| Use | NA | No evidence | ||
| Lapse | No difference. 1 RCT found no difference between groups in number of days to lapse. | Insufficient | ||
| Retention | No difference. 1 RCT reported high rates of retention (94% buspirone vs 93% placebo), but no difference between groups. | Insufficient | ||
| Withdrawal due to AE | No difference. In 1 RCT there were no withdrawals due to AEs. | Insufficient | ||
| Severe AE | Favors placebo. In 1 RCT there were 3 SAEs in participants receiving buspirone vs 0 receiving placebo. | Insufficient | ||
| Cognitive enhancing drugs: memantine, atomoxetine | ||||
| Abstinence | 1 low-ROB RCT24 (N = 81) | No difference. Participants who did not achieve abstinence at baseline (N = 45), there was no difference between groups in the achievement of sustained abstinence (3+ weeks). | Insufficient | Single small RCT with a 2-week placebo lead-in to encourage abstinence after randomization. |
| Use |
1 low-ROB RCT24 (N = 81) 1 unclear-ROB RCT25 (N = 50) |
No difference. There was no difference in cocaine negative UDS′ between groups. | Insufficient | Small body of evidence. Methodological limitations of studies. |
| Relapse | 1 low-ROB RCT24 (N = 81) | No difference. Among participants who achieved abstinence at baseline (N = 36), there was no difference between groups in relapse or time to relapse. | Insufficient | Small body of evidence. Indirectness (of results to general population—participants had achieved abstinence prior to the outpatient phase). Relapse is defined as 2 consecutive cocaine positive UDS′. |
| Retention | 1 low-ROB RCT24 (N = 81) | No difference. There was no difference in retention by group. | Insufficient | Small body of evidence. Methodological limitations of studies. |
| Harms | 1 unclear-ROB RCT25 (N = 50) |
No difference. There was no difference in retention by group. No difference. 0 participants receiving memantine experienced a SAE compared with 2 who received placebo. |
Insufficient | |
| Psychostimulants: dexamphetamine, mazindol, methamphetamine, methylphenidate, mixed amphetamine salts, modafinil, lisdexamphetamine, selegiline | ||||
| Abstinence | 1 SR of 14 studies7 (N = 1549) | Favors psychostimulants. 1 SR reported a combined 3+ week abstinence RR of 1.36 (95% CI 1.05 to 1.77). | Low | Large body of evidence and consistent results even after removing bupropion studies, but many trials were methodologically flawed. Findings from individual drugs favor dexamphetamine (small body of evidence) and mixed amphetamine salts (single study). |
| Use | 1 SR of 8 RCTs7 (N = 526) | No difference. Use of cocaine, combined SMD 0.16 (95% CI − 0.02 to 0.33). | Low | Trend toward small benefit, inconsistent results |
| Retention | 1 SR of 24 studies7 (N = 2205) | No difference. Number of participants who did not complete the trial, combined RR 1.00 (95% CI 0.93 to 1.06) | Moderate |
Methodological limitations of many included studies. Heterogeneous population. No bupropion studies are included in findings of SAEs. |
| Harms |
Withdrawal: 1 SR of 19 RCTs7 (N = 1601) Serious AEs: 1 SR of 6 RCTs7 (N = 444) |
No difference. Number of participants who withdrew due to AEs, combined mean RD 0.00 (95% CI − 0.01 to 0.01). No difference. Number of participants who reported severe AEs, combined mean RD − 0.02 (95% CI − 0.06 to 0.01). |
Moderate | |
| Anticonvulsants and muscle relaxants | ||||
| Baclofen | ||||
| Abstinence | 2 unclear-ROB RCTs27, 28 (N = 230) | No difference. | Low | |
| Use | 2 unclear-ROB RCTs27, 28 (N = 230) | No difference. | Low | |
| Retention | 2 unclear-ROB RCTs27, 28 (N = 230) | No difference. | Low | |
| Withdrawal due to AE | 1 unclear-ROB RCT27 (N = 70) | No difference. | Insufficient | |
| Severe AE | 2 unclear-ROB RCTs27, 28 (N = 230) | No difference. | Low | |
| Carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate, and vigabatrin (drugs combined in analysis) | ||||
| Abstinence | 1 SR5 | NR | No evidence |
These represent the combined results for all drug classes included in the SR.5 SOE was determined by the SR authors |
| Use | 1 SR of 9 RCTs5 (N = 867) | No difference. Use of cocaine (self-reported or objective), combined RR 0.92 (95% CI 0.84 to 1.02)5 | Moderate5 | |
| Retention | 1 SR that included 17 RCTs5 (N = 1695) | No difference. RR 0.95 (95% CI 0.86 to 1.05)5 | Moderate5 | |
| Topiramate | ||||
| Abstinence |
1 low-ROB RCT29 (N = 60) |
Favors topiramate (3 RCTs). Relapse prevention RCTs: combined findings from 2 unclear-ROB RCTs31, 32 (RR 2.56 [95% CI 1.39 to 4.73]) for 3 or more weeks of continuous abstinence |
Low | |
| Use | 1 low-ROB RCT29 (N = 60) | Favors topiramate. | Insufficient | Only 1 small trial |
| Retention | 5 RCTs: 1 high-ROB33; 2 unclear-ROB30, 32; 2 low-ROB29, 34 (N = 617) | No difference. Combined RR 1.01 (95% CI: 0.93 to 1.10). | Moderate | Methodological limitations of several trials. |
| Harms | 1 low-ROB RCT29 (N = 60) | No withdrawals occurred due to AE. No severe AEs occurred. | Insufficient | Only 1 small RCT |
| Vigabatrin | ||||
| Abstinence | 1 high-ROB RCT83 (N = 103) | Favors vigabatrin. Full 3-week end-of-trial abstinence 28% vs 7.5% P ≤ 0.01 | Insufficient | Incomplete data was reported for the full trial period. |
| Use |
1 unclear-ROB RCT84 (N = 186) 1 high-ROB RCT83 (N = 103) |
No difference. Total events: 76 (treatment), 86 (placebo). RR 0.88; 95% CI 0.69 to 1.13 | Low | Analysis from SR5 |
| Retention |
1 unclear-ROB RCT84 (N = 186) 1 high-ROB RCT83 (N = 103) |
No difference. Total events: 98 (treatment), 108 (placebo). RR 0.74; 95% CI 0.53 to 1.02. | Low | |
| Harms | 1 unclear-ROB RCT84 (N = 186) | No difference. RR 0.97; 95% CI 0.88 to 1.08 | Insufficient | |
| Medications FDA-approved for other substance use disorders | ||||
| Acamprosate | ||||
| Abstinence | – | No evidence | – | |
| Use | 1 low-ROB RCT50 (N = 60) | No difference. % UDS(−): 22% vs 23%, P = 0.44 | Insufficient | Only 1 small RCT |
| Retention | 1 low-ROB RCT50 (N = 60) | No difference. 18/34 (53%) vs 18/26 (69%), P = NS | Insufficient | Only 1 small RCT |
| Harms | – | No evidence | – | |
| Buprenorphine plus naloxone, 2 doses | ||||
| Abstinence | 1 low-ROB RCT49 (N = 302) | No difference. Rates of abstinence during weeks 5–8 similar between placebo group (16%) and Bup 4 mg 17.9%, (P = 0.36) and Bup 16 mg 18.6%, (P = 0.32) | Insufficient | Only 1 trial |
| Use | 1 low-ROB RCT49 (N = 302) | Mixed findings. Significantly less use with Bup 16 mg + naloxone 4 mg vs placebo. No difference with lower dose | Insufficient | |
| Retention | 1 low-ROB RCT49 (N = 302) | No difference. Rates of retention similar between placebo (87.3%) vs Bup 4 mg (86.0%) vs Bup 16 mg (88.0%) | Insufficient | |
| Harms | – | No evidence | – | |
| Buprenorphine vs methadone | ||||
| Abstinence | 2 low-ROB RCTs35, 36 (N = 278) | Mixed findings. Longer abstinence with methadone in 1 RCT; no difference in 1 RCT | Insufficient | Mixed findings |
| Use | 1 low-ROB RCT35 (N = 116) | Favors Methadone. Lower use with methadone vs buprenorphine (P < 0.05) | Insufficient | |
| Retention | 2 low-ROB RCTs35, 36 (N = 278) | Mixed findings. Better retention with methadone in 1 RCT; no difference in 1 RCT | Insufficient | Mixed findings |
| Harms | 1 low-ROB RCT36 (N = 162) | Elevated LFT in 1 subject | Insufficient | |
| Disulfiram | ||||
| Abstinence | 3 RCTs37, 41, 85 (N = 296) | No difference. Continuous abstinence disulfiram vs placebo, combined RR from 3 RCTs N = 296, RR 0.96 (95% CI 0.63 to 1.45) | Low | ROB unclear overall |
| Use |
(N = 440) |
No difference. Combined RR from 4 RCTs: 0.95 (95% CI 0.64 to 1.39). The effect varied among studies, and statistical heterogeneity was highly significant (P < 0.001). | Low | Heterogeneous findings among studies |
| Retention |
1 SR4 that included 2 RCTs (N = 87): 1 unclear-ROB (N = 20),85 1 high-ROB86 (N = 67) |
Favors placebo. Treatment retention was lower with disulfiram: Meta-analysis of 7 RCTs, N = 704, RR 0.90 (95% CI 0.83 to 0.99). | Moderate | The combination of findings from all 7 studies (N = 704) was statistically homogeneous (P = 0.90) |
| Harms | 4 RCTs38–41 (N = 548) | Withdrawals due to AE ranged from 0 to 5.9%, and included elevated liver enzymes and rash. Severe AEs not otherwise reported. | Low | – |
| Naltrexone | ||||
| Abstinence |
1 unclear-ROB RCT46 (N = 416) |
No difference. 2 studies found no differences in N weeks to relapse. 1 study found no differences in abstinence (17.9% vs 17.1%, P = 0.918) | Low | Imprecision due to small number of studies; 1 study rated unclear ROB |
| Use | 1 low-ROB RCT45 (N = 80) | No difference. 1 study compared %(+) UDS at weeks 1–4; 5–8; and 9–12 and found no differences between T vs C. | Insufficient | Only 1 small RCT |
| Retention |
1 unclear-ROB RCT46 (N = 416) |
No difference. All 4 studies reported no differences in treatment retention | Low | Imprecision due small number of trials; indirectness due to behavioral co-interventions |
| Harms | 1 low RCT47 (N = 64) | No difference. In 1 trial of 64 pts., 2 in treatment arm and 11 in placebo arm experienced AE, non-significant. | Insufficient | Only 1 small RCT |
| Varenicline | ||||
| Abstinence | – | No evidence | – | |
| Use | 2 unclear-ROB RCTs51, 52 (N = 68) | No evidence. 1 study found trend toward lower use with varenicline (OR = 0.49, P = 0.08); 1 study found no difference (P = 0.84) | Insufficient | Few trials included; inconsistency of findings |
| Retention | 2 unclear-ROB RCTs51, 52 (N = 68) | No difference. 1 study reported 77% total retention with no “significant difference in time to last visit” (P = 0.1); 1 study reported 5 drop out and no differences between groups (P = 0.26) | Insufficient | Unclear risk of bias, small number of studies. |
| Harms | 1 unclear-ROB RCT51 (N = 31) | No difference. 1 trial reported no withdrawals due to AEs. | Insufficient | Unclear risk of bias, only 1 trial, few evens |
| Dopamine agonists | ||||
| Amantadine, bromocriptine, l-dopa/carbidopa, pergolide, cabergoline hydergine, and pramipexole (drugs combined in analysis) | ||||
| Abstinence | 1 SR of 11 RCTs6 (N = 731) | No difference. At 6 weeks: RR 1.12 (95% CI 0.85 to 1.47); at 4 months: RR 1.1 (95% CI 0.61 to 1.98) | Low6 | Strength of evidence was determined by the SR authors6 |
| Use | NR | NR | – | |
| Retention | 1 SR of 20 studies6 (N = 1656) | No difference. RR 1.04 (95% CI 0.94 to 1.14) | Moderate6 | |
| Harms | 1 SR of 7 studies6 (N = 252) | SAEs and withdrawals due to AE NR. | No evidence6 | |
AE, adverse event; CI, confidence interval; DSM, Diagnostic and Statistical Manual of Mental Disorders; MD, mean difference; NR, not reported; P, p value; RCT, randomized control trial; RD, risk difference; RR, relative risk; ROB, risk of bias; SAE, severe adverse event; SMD, standard mean difference; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SR, systematic review; UDS, urine drug screens
*The overall quality of evidence for each outcome is based on the consistency, coherence, and applicability of the body of evidence, as well as the internal validity of individual studies. The strength of evidence is classified as follows16: high, further research is very unlikely to change our confidence on the estimate of effect; moderate, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; insufficient, any estimate of effect is very uncertain