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��ࡱ�>��	���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	��Gbjbj���	4�����G�������F	F	��������������y��/K0^	c"c"c"�"~#~#~#�J�J�J�J�J�J�J_L�OZ�J�~#~#~#~#~#�J��c"�"��J�>�>�>~#��c"��"�J�>~#�J�>�>�>c",�������Z���D7��>�J�J0/K�>[O2>�[O�>�>�	[O��H~#~#�>~#~#~#~#~#�J�J�>~#~#~#/K~#~#~#~#��������������������������������������������������������������������[O~#~#~#~#~#~#~#~#~#F		O:	Management of Opioid Abuse and Dependence: A Review of the Current and Novel Approaches

Ayman Fareed, MD, 
Assistant Professor, Department of Psychiatry, Emory University, School of Medicine/Atlanta VA Medical center
Mailing address:
Atlanta VA Medical Center 116A
1670 Clairmont Rd.
Decatur, GA 30033
Tel.: (404) 321-6111X7104
Fax: (404) 728-4147
Email: HYPERLINK "mailto:ayman.fareed@va.gov"ayman.fareed@va.gov
















Abstract:
In this review the reader will be update about the most recent guidelines for treatment of opioid abuse and dependence. The first phase of treatment which is managing the opioid withdrawal syndrome and detoxification will be described in details. The opioid agonist maintenance treatment with either methadone or buprenorphine for patients who fail abstinent based models will be elaborated. Opioid antagonists like naltrexone maintenance which are another form of treatment for patients who do not qualify for or desire opioid agonist maintenance treatment will also be elaborated. Treatment of special populations such as adolescents and opioid dependent pregnant women is included in this review. Psychotherapeutic interventions will be discussed with emphasis on contingency management (CM) since it is the most studied intervention in this population. Finally new approaches for treatment will be mentioned briefly. 




Key words: management, opioids, current and novel, approaches














Treatment of Opioid withdrawal
Opioid withdrawal is a syndrome related to sudden discontinuation of opioids after prolonged period of use. Short acting opioids such as heroin and oxycodone usually exhibit signs and symptoms of withdrawal within 8-12 hours after the last dose. If untreated, it reaches a peak within 36-72 hours and usually subsides substantially within 5 days. For long acting opioids like methadone, withdrawal may reach a peak between 5-6 days, and the syndrome will not usually subside for 14-21 days. The signs and symptoms of opioid withdrawal may be classified as objective and subjective 1. Objective signs include vomiting, lacrimation, rhinorrhea, pupillary dilatation, piloerection, sweating, diarrhea, yawning, fever, elevated pulse and blood pressure. Subjective symptoms may include dysphoric mood, insomnia, muscle aches and cramps, abdominal pain and colic. The Clinical Opiate Withdrawal Scale (COWS) 2 is usually used to classify the severity of the opioid withdrawal syndrome based on the generated score. A score less than 5, indicates that there is no withdrawal. A score higher than 5 but less than 12 indicates that the patient is in mild withdrawal, 13 to less than 24 indicates moderate withdrawal and a score higher than 25 means severe withdrawal. 

Long acting opioids like methadone and buprenorphine have cross tolerance with other short acting opioids. Their long duration of action would make them appropriate agents for treatment of opioid withdrawal syndrome and detoxification. These 2 medications are approved by the United States (US) Food and Drug Administration (FDA) for treatment of opioid dependence. The best approach to treat the opioid withdrawal is to start by giving the substituting agent (methadone or buprenorphine) as needed for the first 24 hours. COWS could be used every few hours to check for signs and symptoms of withdrawal. Based on the COWS score the substituting agent can be administered as needed. After the first 24 hours the total dose that has been used within the past 24 hours can be calculated. Then, it can be tapered gradually by reducing the total dose by about 20% per day. For example if the patient needed a total methadone dose of 30 mg on day one, then this dose can be reduced by 5 mg/day on subsequent days to zero. While this method of opioid detoxification is most accurate, it needs intensive monitoring and it is usually reserved for inpatient detoxification. For outpatient detoxification, there is no common protocol or specific time frame for that purpose. Several factors may determine the duration of the ambulatory detoxification like how long the patient was using opioids, the total daily dose that was used and the type of the abused opioid (i.e. short acting versus long acting). A thirteen days buprenorphine taper protocol was used in one of the National Institute of Drug Abuse (NIDA) clinical trial network 3. They used buprenorphine 8 mg/day for 2 days, then 16 mg/day for one day, then a taper by 2 mg/day until zero. Several studies 4-6 suggested varying detoxification protocols ranging from 3 to 30 days depending on the severity of the withdrawal syndrome. The goal is to reduce the withdrawal syndrome and minimizes the patient�s suffering. Sigmon et al 7 suggested a shorter detoxification protocol with a goal of switching to naltrexone maintenance. They suggested an initial 2-4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3-5 days up to the target dose of naltrexone.

Symptomatic treatment with an alpha 2 receptor agonist such as clonidine, lofexidine or guanfacine decreases noradrenergic activity and reduces some signs and symptoms of opioid withdrawal. However, several studies reported that this option is not as effective as substitution with mu receptor agonists in reducing the severity of the withdrawal syndrome 8-11. 

Opioid dependence is a chronic disease and frequent relapses have been reported following ambulatory or inpatient detoxification for that matter. Opioid craving is usually the trigger for relapse even after long periods of abstinence. Patients who fail abstinent based models of treatment would be good candidates for opioid maintenance treatment. 

Opioid Maintenance for Management of Opioid Craving 
Craving is a subjective phenomenon which may be defined as an increased desire to use drugs or alcohol while being drug abstinent 12. It is associated with the use of substances which have reward reinforcing (euphoric) properties like alcohol, cocaine and heroin. While craving is a subjective phenomenon, it can be triggered by environmental factors such as being exposed to drug related cues. In the case of opioids, craving may occur due to the need to alleviate withdrawal symptoms (negative craving) or an increased desire to use opioids due to their euphoric effect (positive craving). A number of imaging studies have examined the neurobiologic correlates of heroin craving. Zijlstra et al 13 reported in their imaging study using single photon emission computed tomography (SPECT) that opioid dependent subjects had lower baseline dopamine type 2 receptors (D2R) in the left caudate nucleus compared to normal subjects. They also found that opioid dependent subjects demonstrated higher dopamine release after cue �exposure in the right putamen than controls. They added that chronic craving and anhedonia were positively correlated with dopamine (DA) release. Sell et al14 used positron emission tomography (PET) to study brain activity in opioid addicts being exposed to heroin related and neutral cues. They found that the self reports of �urge to use� correlated strongly with increased regional blood flow in the inferior frontal and orbitofrontal cortex target regions of the mesolimbic dopaminergic system implicated in conditioning and reward. Xiao et al15 studied brain activity in a group of thirsty heroin addicts being exposed to water and drug related cues using functional magnetic resonance imaging (fMRI). They found that drug related cues activated bilateral inferior frontal cortex confirming the critical role of prefrontal cortex in opioid craving. Their results suggest that heroin craving may involve different neural circuits other than the desire from basic physiological derives, such as thirst. 
 
One may understand from these studies that opioid dependent patients may have structural and functional brain abnormalities which could increase their risk for opioid craving and relapse. Several studies reported that opioid maintenance treatment reduces craving for illicit opioids and prevent frequent relapses. Currently, methadone and buprenorphine are approved by the FDA for maintenance treatment of opioid dependence. 


Methadone Maintenance Treatment 
There is evidence that methadone reduces opioid craving. Several studies supported that notion16-26. Other studies 27-38 reported an essential role for the methadone dose on opioid craving and prevention of relapse. They reported that being on higher doses of methadone may protect against craving in patients receiving MMT while being on lower doses or undergoing detoxification may increase the risk of craving and relapse. Therefore, it may be important to address opioid craving and risk of relapse for patients who are requesting detoxification. Also this data may provide guideline for effective methadone dosing and prevention of relapse especially for patients who continue to experience opioid craving while being on lower doses of methadone. Methadone dose seems to be an important factor for blocking the euphoric effect and reduction of opioid craving for patients receiving MMT.

Starting dose of methadone should not exceed 20-30 mg on first day of methadone induction. It is very important to educate the patient about the risk of mixing methadone with other central nervous system depressants like alcohol and benzodiazepines. The steady state of methadone usually takes about 3-5 days. Therefore quick dose titration should be avoided to prevent the risk of methadone overdose due to the cumulative effect of rapid dose escalation. Withdrawal and craving for opioids should be monitored during the induction phase with the goal of blocking all withdrawal signs and minimizing craving. COWS scale could be a useful tool during the induction phase to help with proper dosing. Methadone peak and trough levels are another helpful tool to provide more objective information for dose adjustment. Methadone is usually dispensed once daily for the sake of opioid maintenance treatment but if the ratio of the peak to trough level is more than 2:1, a split dosing could be considered for some patients who may complain of opioid withdrawal near the end of the dosing interval. Methadone is dispensed through licensed clinics and clinicians should be familiar with the federal guidelines for MMT.    

Despite the common agreement that methadone is an effective treatment for opioid dependence, there has been a wide variation for dosing among clinicians. Some clinicians have been conservative and leaning toward the low dose regimen. This practice may have a better safety profile for methadone side effects and overdose. However, patients who are treated with the lower dose range tend to do worse regarding illicit opioid use and retention in treatment. Several studies reported that methadone dose in the range of 60-100 mg daily is safe and effective for methadone maintenance treatment compared to lower dosages 39-46. Based on those reports, the national institute of health (NIH) made a consensus47 to help clinicians with proper methadone dosing. They recommended a guideline for the proper methadone dose to be at least 60 mg daily. Despite the NIH consensus, many methadone programs are still using doses below the recommended guidelines. A survey was done to examine the extent to which U.S. methadone clinics meet established standards for minimum dosage between 1988 and 2005 48. It was found that 40 % of patients receive doses of at least 80 mg daily the threshold identified as recommended practice in recent work, 34 % receive doses below 60 mg daily and 17 % receive doses below 40 mg daily. Some recent studies explored the efficacy and safety of methadone doses above 100 mg daily. Three naturalistic studies 49-51 with a large number of patients reported that doses above 100 mg daily are safe and effective in long term maintenance treatment. They indicated that response to MMT can be optimized when doses are individually titrated against signs and symptoms just like any chronic medical disease. Two recent clinical trials 52,53with a small number of patients reported that doses in the range of 120- 150 mg daily are more effective in reducing heroin self administration and suggest that the mechanism of this increased efficacy is by reduction of the positively reinforcing (euphoric) effect of heroin and not by reduction in opioid withdrawal discomfort. Kennedy etal54 recently combined individualized methadone dosages over 100 mg/day with voucher-based cocaine targeted contingency management (CM) in 58 heroin- and cocaine-dependent outpatients. Participants were randomly assigned to receive a fixed dose increase from 70 mg/day to 100 mg/day, or to be eligible for further dose increases (up to 190 mg/day, based on withdrawal symptoms, craving, and continued heroin use). All dosing was double-blind. The main outcome measure was simultaneous abstinence from heroin and cocaine. They reported that under double-blind conditions, dosages of methadone over 100 mg/day, even when prescribed based on specific signs and symptoms, were not better than 100 mg/day. However, this study was stopped early due to slow recruitment and other limitations include partial failure of randomization. Therefore, its finding requires replication, and may not be generalizable at the present time. 

QT interval prolongation and Torsade de Pointes (TdP) a lethal cardiac arrhythmia have been reported in patients treated with methadone for opioid dependence or pain management 55-66. A dose dependent effect on QT prolongation has been shown in some studies with increased risk for doses above 100 mg/day 67-71. The NIH did not yet provide recommendations for EKG screening for patients who are in MMT. However, an expert panel for EKG screening and monitoring for patients in methadone treatment recommended obtaining a pretreatment EKG for all patients to measure the QT interval and a follow-up EKG within 30 days and annually 72. Additional EKG is recommended if the methadone dosage exceeds 100 mg/day or if patients have unexplained syncope or seizures. If the QT interval is greater than 450 ms but less than 500 ms, the clinician needs to discuss the potential risks and benefits with patients and monitor them more frequently. If the QT interval exceeds 500 ms, the clinician needs to consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. Clinicians should be aware of interactions between methadone and other drugs that possess QT interval�prolonging properties or slow the elimination of methadone. 

Clinicians need to consider the pros and cons of the higher dose range. While the higher dose may increase the risk for cardiotoxicity and may require more EKG screening, the untreated opioid addiction could be much more lethal. Overdose and accidents are the most frequent cause of death among untreated opioid addicts. At the present time, we have data to support the fact that the dose range of 60-100 mg daily is safe and effective for reducing illicit opioid use. 

Buprenorphine Maintenance Treatment 
Buprenorphine has been approved by the US FDA for office-based treatment of opioid dependence in October 2002. It became available in the market in 2003 in 2 products, buprenorphine only (Subutex) and buprenorphine/naloxone combination (Suboxone). Buprenorphine may have a better safety profile than methadone due to its pharmacokinetic and pharmacodynamic properties. It is a partial agonist of the mu opiate receptor and has a ceiling effect, which may reduce the risk for drug overdose 73. It is also safer than methadone with regard to its cardiotoxic effect59. Buprenorphine induction is easy and the therapeutic dose can be achieved within a few days. Patients need to be in opioid withdrawal at the time of buprenorphine induction to avoid precipitating opioid withdrawal since buprenorphine is a partial mu receptor agonist. It is recommended not to exceed 8 mg on the first day of the induction. Dose can be titrated as needed to block opioid withdrawal and minimize craving. Urine drug screens are used to monitor illicit drug use and provide an objective measure for treatment outcome.    

Several studies reported that buprenorphine is a safe and effective medication for office-based treatment of opiate dependence74-77. Most of the initial studies reported that lower doses of buprenorphine78-79 (8 mg or less per day) were not as effective as higher buprenorphine doses (8�16 mg per day) or methadone 80-84. Illicit opiate use, as measured by urine drug screens and dropping out of treatment, were higher for the participants who received lower doses of buprenorphine in those studies. These data have led to studying the safety and efficacy of higher doses of buprenophine. More recent studies reported that a buprenorphine dosage ranging from 16 to 32 mg per day is safer and more effective than lower doses in reducing illicit use and craving for opioids85,86 . The buprenorphine�s insert reports that a dose between 12�16 mg per day is the target for buprenorphine maintenance treatment 87. This dose may block the opioid withdrawal syndrome, but some patients may continue to use illicit opioids in this range. The severity and duration of opioid addiction may reflect the need for a higher or lower buprenorphine dose to achieve an adequate mu receptor blockade, reduce the subjective opioid craving, and prevent relapse on opioids. Comorbid chronic pain may also explain the need to be on a higher buprenorphine dose. A recent multicenter study88 conducted by the National Institute of Drug Abuse (NIDA) clinical trial network reported that the presence of pain predicts buprenorphine dose levels in opioid-dependent patients. They added that patients with pain have opioid use outcomes comparable with those without pain but require higher buprenorphine doses (mean dose 19 mg compared to 12 mg for patients without comorbid pain). Fareed et al 89recently reported that higher doses of buprenorphine (16-32 mg daily) may provide better outcome for illicit opiate use among some patients who would not respond to moderate doses (8-16 mg daily). However, this is a non randomized observational study and may not be generalizable. Saxon et al90 recently conducted a multicenter clinical trial to study the effect of buprenorphine and methadone on liver injury. In this study the mean dose of buprenorphine was 22.1 mg daily. The study showed that there was no evidence of liver damage either for buprenorphine or methadone during the 6 month period of the study. The study also showed that the methadone maintained participants were retained longer than the buprenorphine maintained participants. A recent review study91 showed that the higher dose of buprenorphine may improve retention in treatment compared to the lower doses. Weiss et al92 reported recently in a multicenter study for patient dependent on prescription opioids that buprenorphine maintenance is superior to tapering even after being in maintenance treatment for 12 weeks. Each time those patients were tapered off buprenorphine their self report and urine drug screens showed significantly worse outcome than when they were on buprenorphine maintenance regardless of receiving counseling or not. This study confirms the superiority of opioid maintenance treatment compared to abstinent based treatment.  Woody et al93 reported that continuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification in youth 15 to 21 years old. In this stud patients the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. Buprenorphine is currently approved for treatment of adolescents age 16 and above diagnosed with opioid dependence.        

Buprenorphine has a ceiling effect, i.e., the linear relationship between the dose and the effect disappears at doses greater than 24 mg per day. The ceiling effect reduces the risk for overdose. Therefore, doses greater than 24 to 32 mg per day would not add to its respiratory depressant effect 94-96. Some studies reported an increased risk for respiratory depression and death due to mixing buprenorphine with other central nervous system depressants such as benzodiazepines and alcohol 97,98. Therefore, patients on the high dose range should be monitored for the increased risk of overdose due to the drug-drug interaction with other central nervous system depressants. Achieving the best treatment outcome without jeopardizing safety should be the goal for office-based buprenorphine treatment. 

Treatment of Opioid Dependent Pregnant Women
Illicit opioid use during pregnancy has been reported to be associated with adverse outcome to the mother and the fetus. Intrauterine growth retardation, premature delivery, low birth weight, small head circumference, still birth and fetal death are common fetal complications among opioid pregnant women 99-101. Pregnant women with active illicit opioid use are at higher risk for poor nutrition, health status and inadequate prenatal care.  They usually have poor social support and may lose the custody of their infants due to their active opioid addiction. Offering treatment for opioid dependent pregnant women may drastically improve the outcome for the mothers and their babies. MMT has been the standard treatment for opioid dependent pregnant women. It reduces the high risk of relapse in this population which has been reported to be 41-96% after medication assisted detoxification 102-104. MMT can also reduce the adverse fetal outcome like premature delivery. Jones et al 105compared the neonatal and maternal outcome for a group of opioid pregnant women receiving MMT versus another group who received methadone assisted detoxification. They found that the group who received methadone assisted withdrawal had a poorer maternal outcome compared to the methadone maintained group. They concluded that MMT should be strongly considered as the primary treatment approach for opioid dependent women. MMT has been reported to be associated with neonatal abstinent syndrome (NAS) characterized by nervous system hyperirritability, gastrointestinal, respiratory and autonomic nervous system dysfunction. NAS may require pharmacologic treatment and prolonged hospitalization after delivery. Induction of methadone during pregnancy is similar to what we described before in the methadone maintenance section. Methadone metabolism and clearance usually increase during the third trimester of pregnancy106 which lead to a reduced plasma level107,108. Therefore, the methadone dose may need to be increased during the third trimester to maintain a therapeutic plasma level. Some pregnant women may complain of opioid withdrawal during their third trimester. A methadone peak and trough levels are indicated in these circumstances with the possibility of a dose increase and/or split dosing to block the opioid withdrawal and the risk of relapse on illicit opioids.   

MMT has been recommended as the only standard treatment for opioid dependent pregnant women. This recommendation may change due to a recently published multicenter, international, double blind randomized clinical trial 109.  In this study Jones et al compared the maternal and neonatal treatment outcome for a group of opioid dependent pregnant women receiving MMT and another group receiving BMT. They found that the group who received BMT needed significantly less morphine for managing their NAS, had a significantly shorter hospital stay, and had a significantly shorter duration of treatment for the NAS. However, treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). Most of the women who left the buprenorphine group reported that they were not satisfied with treatment. The higher rate of satisfaction with methadone confirmed the important role it plays in treating pregnant women who are dependent on opioids. Moreover, given the partial agonistic activity of buprenorphine and its ceiling effect at maximal doses, it may not be the optimal treatment for all pregnant women with opioid dependence. They concluded that buprenorphine is an acceptable treatment for opioid dependence in pregnant women. Based on this new data, BMT might be recommended as an additional treatment for some opioid dependent pregnant women.   

Naltrexone Maintenance Treatment
Naltrexone is a mu opioid receptor antagonist. It prevents the euphoric effects of opioids and reduces their reinforcing properties by blocking the mu receptors in the brain. Overtime this leads to extinction of the drug seeking behavior and reduces craving for opioids. It is an ideal form of treatment for some patients who do not want or may not qualify for opioid maintenance. For example, the families of some adolescents may not like to consider agonist maintenance treatment as the first line of treatment for their children. Also impaired professional programs (for physicians and nurses) may require monitored naltrexone maintenance treatment before the impaired physician or nurse would be able to return to practicing medicine. Opioid agonist treatment is prohibited in some countries e.g. Russia, which would make naltrexone maintenance the only viable evidence, based form of treatment in these countries. Compliance with taking the medicine is the key for successful antagonist maintenance treatment. Naltrexone is available in 3 forms at present time, a tablet, an extended release injection and a subcutaneous depot implant. The target dose of the naltrexone tablet is 50 mg daily. Poor compliance with the daily use of the tablet has been the main problem that hinders the success of naltrexone maintenance treatment. Therefore, there has been a new interest in studying the extended release injection and depot implant forms in this population. Krupitsky et al110 recently compared in a double blind randomized clinical trial the treatment outcome for naltrexone 1000 mg implant to 50 mg daily oral tablet or placebo. They found that the group who received the implant did significantly better as regard retention in treatment and negative urine drug screens for opioids during the 6 months period of the study. Some patients developed wound infections or local irritation, but none were serious and all resolved with treatment. Hulse et al111 in Australia reported similar outcome. They compared oral tablet 50 mg/day to naltrexone 2.3 g single dose implant in 70 patients over a 6 months clinical trial.  The naltrexone implant effectively reduced relapse to regular heroin use compared with oral naltrexone and was not associated with major adverse events. Krupitsky et al112 also reported in another multicenter double blind placebo controlled clinical trial in Russia that the extended release injectable naltrexone 380 mg yielded significantly better outcome compared to placebo. The group who received the naltrexone injection had significantly better retention in treatment, less opioid positive urine drug screens and less craving for opioids. Comer et al113 compared naltrexone injection 384 mg, and 192 mg to placebo in a double blind clinical trial over 8 weeks. They found that retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Adverse events were minimal and generally mild. 

Psychotherapeutic interventions:
MMT programs offer various psychotherapeutic modalities of treatment. Some programs may recommend Alcoholic Anonymous (AA) meetings as an important resource available in the community for free. Individual and group counseling sessions are also provided by the majority of MMT programs. Some programs may offer case management for their patients. The quality of these services differs among programs and it depends on various factors like the funding status, and the staff to patients ratio. Buprenorphine is being offered in office based settings. Providers of buprenorphine office based treatment should have the resources to refer patients for counseling as a part of the waiver requirement to prescribe the medicine. Contingency management (CM) has been the most studied modality of psychotherapeutic intervention in this population. CM is to offer incentives like money, or vouchers for patients who provide negative UDS114,115.  Some studies used take home doses as an incentive for providing negative UDS116. A meta-analysis117 reported that CM is more effective for treatment of cocaine and opioid compared to nicotine or multiple drugs. Since cocaine addiction is a common comorbidity with opioid dependence, several clinical trials looked at using CM for patients with comorbid opioid and cocaine dependence. Those studies showed a good outcome for both disorders when CM was combined with opioid agonist treatment (either with methadone or buprenorphine)114-118. Epstien et al 119reported that combing CM with methadone dose increase up to 100 mg/day improved treatment outcome for both cocaine and opioid dependence. However, the same authors in a newer study did not find any further improvement for the opioid outcome when the methadone dose was increased up to 190 mg/day. Unexpectedly the group who received the combined CM and doses above 100 mg/day did significantly worse than the group which received CM and doses 70 to 100 mg/day54.   

New Approaches for treatment of opioid dependence: 
A new interest in immunotherapy has been recently investigated to discover new treatment for drug addiction and overdose. Kosten et al reported in 2 review articles 120,121 how immunotherapy techniques can be used to create passive monoclonal antibodies for different drugs like cocaine, heroin and nicotine. These antibodies can block illicit drugs from reaching the brain and therefore, reduce the morbidity and mortality associated with illicit drug intoxication122. Clinical trials are currently in progress to study this new intervention for treatment of stimulant addiction123. This new approach in still under investigation and has not been approved by the FDA at present time.  

Another interest in studying a new approach for patients who are resistant to traditional MMT emerged in Europe and Canada. This new approach entails adding heroin maintenance on top of MMT for some patients who would not respond to the target dose of MMT. Two recent meta-analyses124,125 reported that adding heroin on top of flexible methadone dosing may have added value and improve outcome compared to MMT alone for treatment resistant heroin dependent individuals. This practice has not been studied in the US yet. 



















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