Zohaib Sohail, MD

Communities across the United States have experienced a near-epidemic of opioid abuse. Deaths from opioid overdose have doubled since 2000 and increased 14% from 2013 to 2014.¹ Treatment strategies for opioid use disorder (OUD) target individual well-being with the goal of preventing relapse. Most treatment approaches help patients gain self-confidence and have been described by patients as “giving them their life back.”

Broadly, the major phases of treatment for OUD are similar to those for other substance use disorders, and involve acute detoxification followed by long-term maintenance of sobriety. There are 3 main phases of treatment for OUD:

• treatment engagement
• stabilization and harm reduction
• sustained abstinence.

Long-term maintenance of sobriety in OUD could involve medications that are FDA-approved for this indication: methadone, buprenorphine, and naltrexone. Psychosocial interventions can be used individually and in combination with pharmacotherapy. Because OUD is a chronic disorder typically characterized by intermittent relapse, patients could move back and forth between the different phases of treatment.

In this article, we highlight the medication and non-medication treatment options for the long-term management of OUD.

Defining abuseExogenous opioids are synthetic substances used for their analgesic and morphine-like properties. Opioids are indicated for the treatment of certain pain conditions and exist in varying potencies and delivery systems, which are tailored for specific types of pain.² Opioids work through activity at opioid receptors found in the brain, spinal cord, gut, and other organs. Agonism of specific opioid receptors results in a decreased perception of pain and contributes to their abuse potential.

Because of their abuse potential, prescription of opioids is governed by the Controlled Substances Act³ of the United States. Despite these regulations, approximately 4.5% of U.S. adults from a nationally representative sample were found to be misusing prescription opioids.⁴ Another study used data from the National Survey on Drug Use and Health and showed an increasing prevalence of OUD involving prescription drugs and resulting in increased mortality.⁵ The mortality rate from prescription opioids was found to be higher than for all other illicit drugs combined in 2013.⁶ Recently, Congress passed the Comprehensive Addiction and Recovery Act, which is intended to address the opioid crisis by expanding access to treatments for opioid overdose and addiction treatment services.⁷

The term “opioid use disorder” is found in DSM-5⁸ and replaces the previous diagnoses of opioid abuse and dependence in DSM-IV-TR.⁹ OUD is characterized by a strong desire to continue using opioids despite problems associated with their use. Patients with OUD often experience cravings for opioids, tolerance, repeated failures at cutting down or limiting use, and decreased involvement in social activities.

Maladaptive use of opioids can result in physiologic dependence and lead to withdrawal symptoms, including anxiety, drug craving, insomnia, rhinorrhea, lacrimation, diarrhea, and piloerection. However, physiologic dependence might not necessarily lead to development of OUD, which can be diagnosed when enough other diagnostic criteria present in the absence of physiologic dependence.

Misuse of prescription opioids is more prevalent among patients who meet criteria for other substance use disorders than among patients who do not.¹⁰ Misuse of prescription opioids often results in greater health care utilization, including the need for emergency services, hospitalization, and detoxification.

Assessing for OUDThe Addiction Severity Index was designed to classify and monitor misuse of opioids. The Index has poor sensitivity; it detects recent opioid use but fails to differentiate patients using prescribed opioids from those who are abusing opioids.¹¹ By comparison, the Current Opioid Misuse Measure (COMM) was developed to monitor opioid use in chemical dependency treatment settings.¹² The COMM has reliable internal consistency¹³ and validity and can be used to assess use of opioids outside of routine medical care. To gauge the severity of withdrawal symptoms, the Objective Opioid Withdrawal Scale or Clinical Opiate Withdrawal Scale¹⁴ can be used. Table 1 summarizes some standardized tools used to assess OUD.

Neurobiological considerationsOpioids work through activity at mu, kappa, and delta opioid receptors. These receptors are present in both the peripheral and the central nervous system. Exogenous opioids work through activity at G protein-coupled receptors and by activating specific neurotransmitter systems. The effect of a given opioid drug is dependent on the type and location of receptors it modulates and can range from CNS depression to euphoria.

For example, mu receptor activation produces sedation, euphoria, or analgesia depending upon the location, frequency, and duration of receptor occupancy. Activation of CNS mu receptors can cause miosis and respiratory depression, whereas mu receptor activation in the peripheral nervous system can cause constipation and cough suppression. Mu receptor stimulation through various G-proteins triggers the second messenger cascade, generating enzymes such as cyclic adenosine monophosphate.

Clinical considerationsTreating OUD is challenging because of the ease with which patients can obtain opioids and because sometimes OUD occurs iatrogenically. Engaging patients in treatment is an important step in recovery, but it does not necessarily lead to reduction in opioid use. The engagement stage can involve outreach workers to encourage further treatment. Developing a therapeutic alliance and appropriately incentivizing patients also promotes entry into treatment. Motivational interviewing is used often in substance use treatment programs and can help engage patients in treatment and evaluate their willingness to change problematic behaviors.

Managing acute withdrawal symptoms. Withdrawal symptoms usually are not life threatening, but can be in the context of other medical conditions, such as autonomic instability, hypertension, cardiovascular disease, and dehydration. Withdrawal symptoms also can be life-threatening during in utero exposure to a fetus. Pharmacotherapeutic options to treat opioid withdrawal symptoms include long-acting opioids, such as methadone and buprenorphine,¹⁵ which can be administered in an ambulatory setting. The combination of buprenorphine and naloxone also can be used to treat opioid withdrawal symptoms.

The alpha-2 agonist¹⁶ clonidine, although not FDA-approved for OUD or opioid withdrawal, could be used to shorten the duration of withdrawal symptoms. Clonidine also decreases methadone withdrawal and can be combined with naloxone to target naloxone-induced opioid withdrawal symptoms.^17,18 Nalbuphine and butorphanol should be avoided during opioid withdrawal because they antagonize opioid receptors and can precipitate withdrawal symptoms.^19,20

Maintenance phase involves long-term stabilization and relapse prevention. Treatment options include medication and non-medication interventions.²¹

Non-pharmacologic treatment options,²² principally psychosocial interventions, can be used on their own or in combination with medications for maintenance treatment of OUD. Psychosocial interventions include structured, professionally administered interventions such as cognitive-behavioral therapy (CBT), aversion therapy, and day-treatment programs. Interventions such as peer counseling and self-help groups also are considered psychosocial interventions, but do not require the same type of professional training.

Peer support groups such as Narcotics Anonymous (NA) help members achieve and maintain sobriety and often focus on a traditional 12-step format or on the more recent Matrix Model,^23,24 which is an intensive outpatient treatment program based on components of relapse prevention, motivational interviewing, CBT, and psychoeducation.

In these peer support models, group members discuss patterns of substance use and help one another recognize and overcome problematic behaviors. Groups may vary in terms of their specific approach. For example, NA encourages group members to focus on addiction itself while Methadone Anonymous prefers participants also discuss pharmacologic treatment experiences. Additional services for finding housing and assisting with job placement are also part of some relapse prevention strategies.

Although studies on the use of abstinence-based treatments are limited, abstinence-based therapy is an option for patients wishing to undergo chemical dependency treatment without taking prescription medications to address cravings or withdrawal symptoms.²⁵ However, abstinence-based treatments have been shown to be less effective in improving outcomes than medication-assisted treatment (MAT).²⁶ MAT combines medications and behavioral therapies for treating substance use disorders.

Pharmacologically, OUD can be treated with opioid agonist and antagonist medications. As summarized in Tables 2-4,^27-31 these medications differ based on their pharmacokinetic and pharmacodynamic profiles and intrinsic activity at mu opioid receptors. Opioid system agonists, such as methadone and buprenorphine, decrease cravings by mimicking the activity of exogenous opioids. The opioid antagonists naloxone and naltrexone reinforce abstinence by inhibiting the euphoric effects associated with opioid use. The medication of choice for a given patient depends on:

• treatment adherence
• clinical setting
• degree of withdrawal symptoms
• motivation.²⁶

If a patient is actively seeking abstinence from opioids, either agonist or antagonist treatment can be used. In cases where a patient is not seeking abstinence, then preference should be given to opioid agonists to prevent overdose.²⁶

Evidence suggests MAT can improve outcomes with OUD when compared with abstinence treatment alone. Several randomized, controlled, trials showed methadone and buprenorphine were more effective at treating OUD compared with treatment without medication. To date, 3 medications have been FDA-approved for treating OUD: methadone, buprenorphine, and naltrexone.²⁶ All 3 medications differ in their pharmacokinetic and pharmacodynamic profiles and intrinsic activities at central mu-opioid receptor, as summarized in Tables 2-4.^27-31

MethadoneMethadone reduces the euphoric effects of opioid use because it binds to and blocks opioid receptors. Methadone is an opioid replacement strategy; higher dosages are used for maintenance treatment to prevent additional dosages of opioids from causing euphoria. Methadone typically is administered once daily. However, in certain circumstances, such as rapid metabolism or pregnancy, it can be given as a twice-daily dosing regimen. Specific ABCB1 variants and DRD2 genetic polymorphisms (simultaneous occurrence of ≥2 genetically determined phenotypes) might determine the dosage requirements of methadone.³²

Methadone during pregnancy. Methadone is the treatment of choice for opioid-dependent women during pregnancy³³ and is listed as pregnancy category C because it can result in physiologic dependence of the newborn, although there are no documented controlled studies in humans to assess this risk. Methadone can be used while breast-feeding as long as patients are HIV-negative and not abusing other drugs.^34,35 Because the methadone concentration in breast milk generally is low, the medication can be administered to nursing mothers after a careful consideration of risks and benefits.

Methadone administration. There are stringent eligibility criteria for methadone administration; not all physicians are authorized to prescribe methadone. Its use is federally regulated and only licensed treatment programs and licensed inpatient detoxification units can prescribe and dispense methadone in controlled settings and under the direct supervision of clinical personnel (Table 5).³⁶ Patients meeting eligibility criteria can attend a specialized methadone clinic.

One of the challenges when using methadone for long-term management of OUD is tapering the dosage and attempting to discontinue the medication. Discontinuation of methadone leads to withdrawal symptoms and requires a carefully tailored tapering schedule. The literature on methadone tapering is limited. Tapering schedules could differ from practice to practice and, in many cases, are highly individualized based on the need and response of specific patients.

Dosage reduction schedules can last from 2 to 3 weeks to 6 months. Studies indicate rapid reduction worsens treatment outcomes and protracted tapering is associated with better outcomes. A suggested tapering schedule could involve decreasing the dosage by 20% to 25% until reaching a dosage of 30 mg/d, then decreasing by 5 mg/d every 3 to 5 days until reaching a dosage of 10 mg/d, before finally decreasing by 2.5 mg/d every 3 to 5 days.

Some randomized trials have shown better outcomes with long-term treatment. The goal of many programs is transitioning from maintenance treatment to abstinence. However, programs targeting maintenance rather than abstinence have been shown to be more effective.

The FDA has no defined limits for treatment duration with either methadone or buprenorphine. Therefore, the decision to taper or discontinue either medication should be made carefully case by case, using sound clinical judgment. Studies show that methadone treatment could reduce the spread of HIV,^37,38 decrease criminal behaviors,³⁹ and reduce overall mortality rates.⁴⁰ A follow-up study comparing individuals randomly assigned to receive methadone or buprenorphine for OUD showed reduced risk of mortality overall⁴⁰ in both groups.

Adverse events reported during treatment with methadone include decreased libido, erectile dysfunction, constipation, drowsiness, QTc prolongation, and torsade de pointes.⁴¹ Therefore, the FDA recommends obtaining a detailed medical history and baseline electrocardiogram (ECG), with a repeat ECG within the first month of treatment and then annually. Informing patients about the possibility of arrhythmias is part of the informed consent process before starting methadone.

Clinicians also should be vigilant when using methadone in combination with other medications that can prolong the QTc interval (eg, some antipsychotics). Methadone has a greater risk of fatal overdose then buprenorphine. A large-scale study of >16,000 patients reported a 4-fold increase in mortality resulting from methadone overdose compared with buprenorphine.⁴² 

BuprenorphineBuprenorphine is a partial opioid agonist at the mu opioid receptor. A full opioid agonist binds and fully activates the opioid receptors; an antagonist blocks the same. An opioid receptor partial agonist partially activates the receptor. Therefore, an opioid system partial agonist is a functional antagonist and, at lower dosages, has weak agonist effects; at higher dosages, a partial agonist antagonizes other endogenous and exogenous opioids that compete for binding at the same receptor.⁴³ Because of the partial agonist effect, buprenorphine could result in less physical dependence and less withdrawal symptoms.

Administration. In contrast to methadone, buprenorphine can be prescribed by physicians for long-term management of OUD in the United States. Buprenorphine is available in 2 formulations: a sublingual form for daily use and a long-acting form that causes less withdrawal symptoms and cravings. In May 2016 the FDA approved the first buprenorphine implant for use in opioid dependence.^44,45

To prevent withdrawal symptoms, a 24-hour period of opioid abstinence is recommended before starting buprenorphine or buprenorphine/naloxone treatment.⁴⁶ Although lacking empirical evidence, catechol-O-methyltransferase (COMT) inhibitors, such as entacapone, have an anti-craving affect and are used by some clinicians to improve adherence with buprenorphine. This is because of their ability to balance dopamine, which is central to the reward pathway responsible for cravings. Although use of COMT inhibitors might make sense intuitively, such use is off-label and should be based on clinical judgment and a review of the available literature. A study showed that tapering buprenorphine for 4 weeks in combination with naltrexone improved the abstinence rate.⁴⁷

Adverse effects. Some of the adverse events reported during treatment with buprenorphine include fever, back pain, nausea, cough, sedation, difficulty with urination, and constipation. Respiratory depression is a less common effect of buprenorphine, compared with full opioid agonists, because of the medication’s mechanism of action as a partial agonist.⁴⁸ As a result, buprenorphine has been shown to have a lower risk of fatal overdose than methadone.⁴⁹ Studies have shown buprenorphine to be more likely than methadone to reduce neonatal abstinence syndromes.⁵⁰

NaltrexoneNaltrexone is an opioid antagonist and is an option to promote relapse prevention. Because of its antagonist properties, naltrexone treatment should always start after opioid detoxification because it can potentiate immediate withdrawal symptoms. Naltrexone is available in oral and long-acting formulations, the latter of which may be considered in patients who have difficulty with adherence.³⁷

Oral naltrexone is taken as a single 50 mg-tablet once daily, whereas dosing for long-acting naltrexone in injectable and implantable formulations varies. These long-acting naltrexone formulations typically are administered monthly. Some of the adverse events reported during treatment with naltrexone are nausea, liver damage, and injection site pain.⁵¹

Buprenorphine/naloxoneBecause of buprenorphine’s agonist effects, it has a relatively high abuse potential compared with other opioids.⁵² Naloxone, on the other hand, is an opioid antagonist and is poorly absorbed when given orally and is associated with withdrawal symptoms if used intravenously. Therefore, naloxone is added to buprenorphine to decrease the likelihood of abuse when both are used as a combination product.⁵³

Buprenorphine is combined with naloxone in a ratio of 4:1. Induction begins by using a 2 mg/0.5 mg tablet with dosage titration until symptoms abate. A combination of buprenorphine and naloxone also is available in film and tablet formulations. Patients must abstain from other opioids for at least 24 hours before initiating buprenorphine/naloxone treatment to prevent the precipitation of withdrawal symptoms.

Communities across the United States have experienced a near-epidemic of opioid abuse. Deaths from opioid overdose have doubled since 2000 and increased 14% from 2013 to 2014.¹ Treatment strategies for opioid use disorder (OUD) target individual well-being with the goal of preventing relapse. Most treatment approaches help patients gain self-confidence and have been described by patients as “giving them their life back.”

Broadly, the major phases of treatment for OUD are similar to those for other substance use disorders, and involve acute detoxification followed by long-term maintenance of sobriety. There are 3 main phases of treatment for OUD:

• treatment engagement
• stabilization and harm reduction
• sustained abstinence.

Long-term maintenance of sobriety in OUD could involve medications that are FDA-approved for this indication: methadone, buprenorphine, and naltrexone. Psychosocial interventions can be used individually and in combination with pharmacotherapy. Because OUD is a chronic disorder typically characterized by intermittent relapse, patients could move back and forth between the different phases of treatment.

In this article, we highlight the medication and non-medication treatment options for the long-term management of OUD.

Defining abuseExogenous opioids are synthetic substances used for their analgesic and morphine-like properties. Opioids are indicated for the treatment of certain pain conditions and exist in varying potencies and delivery systems, which are tailored for specific types of pain.² Opioids work through activity at opioid receptors found in the brain, spinal cord, gut, and other organs. Agonism of specific opioid receptors results in a decreased perception of pain and contributes to their abuse potential.

Because of their abuse potential, prescription of opioids is governed by the Controlled Substances Act³ of the United States. Despite these regulations, approximately 4.5% of U.S. adults from a nationally representative sample were found to be misusing prescription opioids.⁴ Another study used data from the National Survey on Drug Use and Health and showed an increasing prevalence of OUD involving prescription drugs and resulting in increased mortality.⁵ The mortality rate from prescription opioids was found to be higher than for all other illicit drugs combined in 2013.⁶ Recently, Congress passed the Comprehensive Addiction and Recovery Act, which is intended to address the opioid crisis by expanding access to treatments for opioid overdose and addiction treatment services.⁷

The term “opioid use disorder” is found in DSM-5⁸ and replaces the previous diagnoses of opioid abuse and dependence in DSM-IV-TR.⁹ OUD is characterized by a strong desire to continue using opioids despite problems associated with their use. Patients with OUD often experience cravings for opioids, tolerance, repeated failures at cutting down or limiting use, and decreased involvement in social activities.

Maladaptive use of opioids can result in physiologic dependence and lead to withdrawal symptoms, including anxiety, drug craving, insomnia, rhinorrhea, lacrimation, diarrhea, and piloerection. However, physiologic dependence might not necessarily lead to development of OUD, which can be diagnosed when enough other diagnostic criteria present in the absence of physiologic dependence.

Misuse of prescription opioids is more prevalent among patients who meet criteria for other substance use disorders than among patients who do not.¹⁰ Misuse of prescription opioids often results in greater health care utilization, including the need for emergency services, hospitalization, and detoxification.

Assessing for OUDThe Addiction Severity Index was designed to classify and monitor misuse of opioids. The Index has poor sensitivity; it detects recent opioid use but fails to differentiate patients using prescribed opioids from those who are abusing opioids.¹¹ By comparison, the Current Opioid Misuse Measure (COMM) was developed to monitor opioid use in chemical dependency treatment settings.¹² The COMM has reliable internal consistency¹³ and validity and can be used to assess use of opioids outside of routine medical care. To gauge the severity of withdrawal symptoms, the Objective Opioid Withdrawal Scale or Clinical Opiate Withdrawal Scale¹⁴ can be used. Table 1 summarizes some standardized tools used to assess OUD.

Neurobiological considerationsOpioids work through activity at mu, kappa, and delta opioid receptors. These receptors are present in both the peripheral and the central nervous system. Exogenous opioids work through activity at G protein-coupled receptors and by activating specific neurotransmitter systems. The effect of a given opioid drug is dependent on the type and location of receptors it modulates and can range from CNS depression to euphoria.

For example, mu receptor activation produces sedation, euphoria, or analgesia depending upon the location, frequency, and duration of receptor occupancy. Activation of CNS mu receptors can cause miosis and respiratory depression, whereas mu receptor activation in the peripheral nervous system can cause constipation and cough suppression. Mu receptor stimulation through various G-proteins triggers the second messenger cascade, generating enzymes such as cyclic adenosine monophosphate.

Clinical considerationsTreating OUD is challenging because of the ease with which patients can obtain opioids and because sometimes OUD occurs iatrogenically. Engaging patients in treatment is an important step in recovery, but it does not necessarily lead to reduction in opioid use. The engagement stage can involve outreach workers to encourage further treatment. Developing a therapeutic alliance and appropriately incentivizing patients also promotes entry into treatment. Motivational interviewing is used often in substance use treatment programs and can help engage patients in treatment and evaluate their willingness to change problematic behaviors.

Managing acute withdrawal symptoms. Withdrawal symptoms usually are not life threatening, but can be in the context of other medical conditions, such as autonomic instability, hypertension, cardiovascular disease, and dehydration. Withdrawal symptoms also can be life-threatening during in utero exposure to a fetus. Pharmacotherapeutic options to treat opioid withdrawal symptoms include long-acting opioids, such as methadone and buprenorphine,¹⁵ which can be administered in an ambulatory setting. The combination of buprenorphine and naloxone also can be used to treat opioid withdrawal symptoms.

The alpha-2 agonist¹⁶ clonidine, although not FDA-approved for OUD or opioid withdrawal, could be used to shorten the duration of withdrawal symptoms. Clonidine also decreases methadone withdrawal and can be combined with naloxone to target naloxone-induced opioid withdrawal symptoms.^17,18 Nalbuphine and butorphanol should be avoided during opioid withdrawal because they antagonize opioid receptors and can precipitate withdrawal symptoms.^19,20

Maintenance phase involves long-term stabilization and relapse prevention. Treatment options include medication and non-medication interventions.²¹

Non-pharmacologic treatment options,²² principally psychosocial interventions, can be used on their own or in combination with medications for maintenance treatment of OUD. Psychosocial interventions include structured, professionally administered interventions such as cognitive-behavioral therapy (CBT), aversion therapy, and day-treatment programs. Interventions such as peer counseling and self-help groups also are considered psychosocial interventions, but do not require the same type of professional training.

Peer support groups such as Narcotics Anonymous (NA) help members achieve and maintain sobriety and often focus on a traditional 12-step format or on the more recent Matrix Model,^23,24 which is an intensive outpatient treatment program based on components of relapse prevention, motivational interviewing, CBT, and psychoeducation.

In these peer support models, group members discuss patterns of substance use and help one another recognize and overcome problematic behaviors. Groups may vary in terms of their specific approach. For example, NA encourages group members to focus on addiction itself while Methadone Anonymous prefers participants also discuss pharmacologic treatment experiences. Additional services for finding housing and assisting with job placement are also part of some relapse prevention strategies.

Although studies on the use of abstinence-based treatments are limited, abstinence-based therapy is an option for patients wishing to undergo chemical dependency treatment without taking prescription medications to address cravings or withdrawal symptoms.²⁵ However, abstinence-based treatments have been shown to be less effective in improving outcomes than medication-assisted treatment (MAT).²⁶ MAT combines medications and behavioral therapies for treating substance use disorders.

Pharmacologically, OUD can be treated with opioid agonist and antagonist medications. As summarized in Tables 2-4,^27-31 these medications differ based on their pharmacokinetic and pharmacodynamic profiles and intrinsic activity at mu opioid receptors. Opioid system agonists, such as methadone and buprenorphine, decrease cravings by mimicking the activity of exogenous opioids. The opioid antagonists naloxone and naltrexone reinforce abstinence by inhibiting the euphoric effects associated with opioid use. The medication of choice for a given patient depends on:

• treatment adherence
• clinical setting
• degree of withdrawal symptoms
• motivation.²⁶

If a patient is actively seeking abstinence from opioids, either agonist or antagonist treatment can be used. In cases where a patient is not seeking abstinence, then preference should be given to opioid agonists to prevent overdose.²⁶

Evidence suggests MAT can improve outcomes with OUD when compared with abstinence treatment alone. Several randomized, controlled, trials showed methadone and buprenorphine were more effective at treating OUD compared with treatment without medication. To date, 3 medications have been FDA-approved for treating OUD: methadone, buprenorphine, and naltrexone.²⁶ All 3 medications differ in their pharmacokinetic and pharmacodynamic profiles and intrinsic activities at central mu-opioid receptor, as summarized in Tables 2-4.^27-31

MethadoneMethadone reduces the euphoric effects of opioid use because it binds to and blocks opioid receptors. Methadone is an opioid replacement strategy; higher dosages are used for maintenance treatment to prevent additional dosages of opioids from causing euphoria. Methadone typically is administered once daily. However, in certain circumstances, such as rapid metabolism or pregnancy, it can be given as a twice-daily dosing regimen. Specific ABCB1 variants and DRD2 genetic polymorphisms (simultaneous occurrence of ≥2 genetically determined phenotypes) might determine the dosage requirements of methadone.³²

Methadone during pregnancy. Methadone is the treatment of choice for opioid-dependent women during pregnancy³³ and is listed as pregnancy category C because it can result in physiologic dependence of the newborn, although there are no documented controlled studies in humans to assess this risk. Methadone can be used while breast-feeding as long as patients are HIV-negative and not abusing other drugs.^34,35 Because the methadone concentration in breast milk generally is low, the medication can be administered to nursing mothers after a careful consideration of risks and benefits.

Methadone administration. There are stringent eligibility criteria for methadone administration; not all physicians are authorized to prescribe methadone. Its use is federally regulated and only licensed treatment programs and licensed inpatient detoxification units can prescribe and dispense methadone in controlled settings and under the direct supervision of clinical personnel (Table 5).³⁶ Patients meeting eligibility criteria can attend a specialized methadone clinic.

One of the challenges when using methadone for long-term management of OUD is tapering the dosage and attempting to discontinue the medication. Discontinuation of methadone leads to withdrawal symptoms and requires a carefully tailored tapering schedule. The literature on methadone tapering is limited. Tapering schedules could differ from practice to practice and, in many cases, are highly individualized based on the need and response of specific patients.

Dosage reduction schedules can last from 2 to 3 weeks to 6 months. Studies indicate rapid reduction worsens treatment outcomes and protracted tapering is associated with better outcomes. A suggested tapering schedule could involve decreasing the dosage by 20% to 25% until reaching a dosage of 30 mg/d, then decreasing by 5 mg/d every 3 to 5 days until reaching a dosage of 10 mg/d, before finally decreasing by 2.5 mg/d every 3 to 5 days.

Some randomized trials have shown better outcomes with long-term treatment. The goal of many programs is transitioning from maintenance treatment to abstinence. However, programs targeting maintenance rather than abstinence have been shown to be more effective.

The FDA has no defined limits for treatment duration with either methadone or buprenorphine. Therefore, the decision to taper or discontinue either medication should be made carefully case by case, using sound clinical judgment. Studies show that methadone treatment could reduce the spread of HIV,^37,38 decrease criminal behaviors,³⁹ and reduce overall mortality rates.⁴⁰ A follow-up study comparing individuals randomly assigned to receive methadone or buprenorphine for OUD showed reduced risk of mortality overall⁴⁰ in both groups.

Adverse events reported during treatment with methadone include decreased libido, erectile dysfunction, constipation, drowsiness, QTc prolongation, and torsade de pointes.⁴¹ Therefore, the FDA recommends obtaining a detailed medical history and baseline electrocardiogram (ECG), with a repeat ECG within the first month of treatment and then annually. Informing patients about the possibility of arrhythmias is part of the informed consent process before starting methadone.

Clinicians also should be vigilant when using methadone in combination with other medications that can prolong the QTc interval (eg, some antipsychotics). Methadone has a greater risk of fatal overdose then buprenorphine. A large-scale study of >16,000 patients reported a 4-fold increase in mortality resulting from methadone overdose compared with buprenorphine.⁴² 

BuprenorphineBuprenorphine is a partial opioid agonist at the mu opioid receptor. A full opioid agonist binds and fully activates the opioid receptors; an antagonist blocks the same. An opioid receptor partial agonist partially activates the receptor. Therefore, an opioid system partial agonist is a functional antagonist and, at lower dosages, has weak agonist effects; at higher dosages, a partial agonist antagonizes other endogenous and exogenous opioids that compete for binding at the same receptor.⁴³ Because of the partial agonist effect, buprenorphine could result in less physical dependence and less withdrawal symptoms.

Administration. In contrast to methadone, buprenorphine can be prescribed by physicians for long-term management of OUD in the United States. Buprenorphine is available in 2 formulations: a sublingual form for daily use and a long-acting form that causes less withdrawal symptoms and cravings. In May 2016 the FDA approved the first buprenorphine implant for use in opioid dependence.^44,45

To prevent withdrawal symptoms, a 24-hour period of opioid abstinence is recommended before starting buprenorphine or buprenorphine/naloxone treatment.⁴⁶ Although lacking empirical evidence, catechol-O-methyltransferase (COMT) inhibitors, such as entacapone, have an anti-craving affect and are used by some clinicians to improve adherence with buprenorphine. This is because of their ability to balance dopamine, which is central to the reward pathway responsible for cravings. Although use of COMT inhibitors might make sense intuitively, such use is off-label and should be based on clinical judgment and a review of the available literature. A study showed that tapering buprenorphine for 4 weeks in combination with naltrexone improved the abstinence rate.⁴⁷

Adverse effects. Some of the adverse events reported during treatment with buprenorphine include fever, back pain, nausea, cough, sedation, difficulty with urination, and constipation. Respiratory depression is a less common effect of buprenorphine, compared with full opioid agonists, because of the medication’s mechanism of action as a partial agonist.⁴⁸ As a result, buprenorphine has been shown to have a lower risk of fatal overdose than methadone.⁴⁹ Studies have shown buprenorphine to be more likely than methadone to reduce neonatal abstinence syndromes.⁵⁰

NaltrexoneNaltrexone is an opioid antagonist and is an option to promote relapse prevention. Because of its antagonist properties, naltrexone treatment should always start after opioid detoxification because it can potentiate immediate withdrawal symptoms. Naltrexone is available in oral and long-acting formulations, the latter of which may be considered in patients who have difficulty with adherence.³⁷

Oral naltrexone is taken as a single 50 mg-tablet once daily, whereas dosing for long-acting naltrexone in injectable and implantable formulations varies. These long-acting naltrexone formulations typically are administered monthly. Some of the adverse events reported during treatment with naltrexone are nausea, liver damage, and injection site pain.⁵¹

Buprenorphine/naloxoneBecause of buprenorphine’s agonist effects, it has a relatively high abuse potential compared with other opioids.⁵² Naloxone, on the other hand, is an opioid antagonist and is poorly absorbed when given orally and is associated with withdrawal symptoms if used intravenously. Therefore, naloxone is added to buprenorphine to decrease the likelihood of abuse when both are used as a combination product.⁵³

Buprenorphine is combined with naloxone in a ratio of 4:1. Induction begins by using a 2 mg/0.5 mg tablet with dosage titration until symptoms abate. A combination of buprenorphine and naloxone also is available in film and tablet formulations. Patients must abstain from other opioids for at least 24 hours before initiating buprenorphine/naloxone treatment to prevent the precipitation of withdrawal symptoms.

Communities across the United States have experienced a near-epidemic of opioid abuse. Deaths from opioid overdose have doubled since 2000 and increased 14% from 2013 to 2014.¹ Treatment strategies for opioid use disorder (OUD) target individual well-being with the goal of preventing relapse. Most treatment approaches help patients gain self-confidence and have been described by patients as “giving them their life back.”

Broadly, the major phases of treatment for OUD are similar to those for other substance use disorders, and involve acute detoxification followed by long-term maintenance of sobriety. There are 3 main phases of treatment for OUD:

• treatment engagement
• stabilization and harm reduction
• sustained abstinence.

Long-term maintenance of sobriety in OUD could involve medications that are FDA-approved for this indication: methadone, buprenorphine, and naltrexone. Psychosocial interventions can be used individually and in combination with pharmacotherapy. Because OUD is a chronic disorder typically characterized by intermittent relapse, patients could move back and forth between the different phases of treatment.

In this article, we highlight the medication and non-medication treatment options for the long-term management of OUD.

Defining abuseExogenous opioids are synthetic substances used for their analgesic and morphine-like properties. Opioids are indicated for the treatment of certain pain conditions and exist in varying potencies and delivery systems, which are tailored for specific types of pain.² Opioids work through activity at opioid receptors found in the brain, spinal cord, gut, and other organs. Agonism of specific opioid receptors results in a decreased perception of pain and contributes to their abuse potential.

Because of their abuse potential, prescription of opioids is governed by the Controlled Substances Act³ of the United States. Despite these regulations, approximately 4.5% of U.S. adults from a nationally representative sample were found to be misusing prescription opioids.⁴ Another study used data from the National Survey on Drug Use and Health and showed an increasing prevalence of OUD involving prescription drugs and resulting in increased mortality.⁵ The mortality rate from prescription opioids was found to be higher than for all other illicit drugs combined in 2013.⁶ Recently, Congress passed the Comprehensive Addiction and Recovery Act, which is intended to address the opioid crisis by expanding access to treatments for opioid overdose and addiction treatment services.⁷

The term “opioid use disorder” is found in DSM-5⁸ and replaces the previous diagnoses of opioid abuse and dependence in DSM-IV-TR.⁹ OUD is characterized by a strong desire to continue using opioids despite problems associated with their use. Patients with OUD often experience cravings for opioids, tolerance, repeated failures at cutting down or limiting use, and decreased involvement in social activities.

Maladaptive use of opioids can result in physiologic dependence and lead to withdrawal symptoms, including anxiety, drug craving, insomnia, rhinorrhea, lacrimation, diarrhea, and piloerection. However, physiologic dependence might not necessarily lead to development of OUD, which can be diagnosed when enough other diagnostic criteria present in the absence of physiologic dependence.

Misuse of prescription opioids is more prevalent among patients who meet criteria for other substance use disorders than among patients who do not.¹⁰ Misuse of prescription opioids often results in greater health care utilization, including the need for emergency services, hospitalization, and detoxification.

Assessing for OUDThe Addiction Severity Index was designed to classify and monitor misuse of opioids. The Index has poor sensitivity; it detects recent opioid use but fails to differentiate patients using prescribed opioids from those who are abusing opioids.¹¹ By comparison, the Current Opioid Misuse Measure (COMM) was developed to monitor opioid use in chemical dependency treatment settings.¹² The COMM has reliable internal consistency¹³ and validity and can be used to assess use of opioids outside of routine medical care. To gauge the severity of withdrawal symptoms, the Objective Opioid Withdrawal Scale or Clinical Opiate Withdrawal Scale¹⁴ can be used. Table 1 summarizes some standardized tools used to assess OUD.

Neurobiological considerationsOpioids work through activity at mu, kappa, and delta opioid receptors. These receptors are present in both the peripheral and the central nervous system. Exogenous opioids work through activity at G protein-coupled receptors and by activating specific neurotransmitter systems. The effect of a given opioid drug is dependent on the type and location of receptors it modulates and can range from CNS depression to euphoria.

For example, mu receptor activation produces sedation, euphoria, or analgesia depending upon the location, frequency, and duration of receptor occupancy. Activation of CNS mu receptors can cause miosis and respiratory depression, whereas mu receptor activation in the peripheral nervous system can cause constipation and cough suppression. Mu receptor stimulation through various G-proteins triggers the second messenger cascade, generating enzymes such as cyclic adenosine monophosphate.

Clinical considerationsTreating OUD is challenging because of the ease with which patients can obtain opioids and because sometimes OUD occurs iatrogenically. Engaging patients in treatment is an important step in recovery, but it does not necessarily lead to reduction in opioid use. The engagement stage can involve outreach workers to encourage further treatment. Developing a therapeutic alliance and appropriately incentivizing patients also promotes entry into treatment. Motivational interviewing is used often in substance use treatment programs and can help engage patients in treatment and evaluate their willingness to change problematic behaviors.

Managing acute withdrawal symptoms. Withdrawal symptoms usually are not life threatening, but can be in the context of other medical conditions, such as autonomic instability, hypertension, cardiovascular disease, and dehydration. Withdrawal symptoms also can be life-threatening during in utero exposure to a fetus. Pharmacotherapeutic options to treat opioid withdrawal symptoms include long-acting opioids, such as methadone and buprenorphine,¹⁵ which can be administered in an ambulatory setting. The combination of buprenorphine and naloxone also can be used to treat opioid withdrawal symptoms.

The alpha-2 agonist¹⁶ clonidine, although not FDA-approved for OUD or opioid withdrawal, could be used to shorten the duration of withdrawal symptoms. Clonidine also decreases methadone withdrawal and can be combined with naloxone to target naloxone-induced opioid withdrawal symptoms.^17,18 Nalbuphine and butorphanol should be avoided during opioid withdrawal because they antagonize opioid receptors and can precipitate withdrawal symptoms.^19,20

Maintenance phase involves long-term stabilization and relapse prevention. Treatment options include medication and non-medication interventions.²¹

Non-pharmacologic treatment options,²² principally psychosocial interventions, can be used on their own or in combination with medications for maintenance treatment of OUD. Psychosocial interventions include structured, professionally administered interventions such as cognitive-behavioral therapy (CBT), aversion therapy, and day-treatment programs. Interventions such as peer counseling and self-help groups also are considered psychosocial interventions, but do not require the same type of professional training.

Peer support groups such as Narcotics Anonymous (NA) help members achieve and maintain sobriety and often focus on a traditional 12-step format or on the more recent Matrix Model,^23,24 which is an intensive outpatient treatment program based on components of relapse prevention, motivational interviewing, CBT, and psychoeducation.

In these peer support models, group members discuss patterns of substance use and help one another recognize and overcome problematic behaviors. Groups may vary in terms of their specific approach. For example, NA encourages group members to focus on addiction itself while Methadone Anonymous prefers participants also discuss pharmacologic treatment experiences. Additional services for finding housing and assisting with job placement are also part of some relapse prevention strategies.

Although studies on the use of abstinence-based treatments are limited, abstinence-based therapy is an option for patients wishing to undergo chemical dependency treatment without taking prescription medications to address cravings or withdrawal symptoms.²⁵ However, abstinence-based treatments have been shown to be less effective in improving outcomes than medication-assisted treatment (MAT).²⁶ MAT combines medications and behavioral therapies for treating substance use disorders.

Pharmacologically, OUD can be treated with opioid agonist and antagonist medications. As summarized in Tables 2-4,^27-31 these medications differ based on their pharmacokinetic and pharmacodynamic profiles and intrinsic activity at mu opioid receptors. Opioid system agonists, such as methadone and buprenorphine, decrease cravings by mimicking the activity of exogenous opioids. The opioid antagonists naloxone and naltrexone reinforce abstinence by inhibiting the euphoric effects associated with opioid use. The medication of choice for a given patient depends on:

• treatment adherence
• clinical setting
• degree of withdrawal symptoms
• motivation.²⁶

If a patient is actively seeking abstinence from opioids, either agonist or antagonist treatment can be used. In cases where a patient is not seeking abstinence, then preference should be given to opioid agonists to prevent overdose.²⁶

Evidence suggests MAT can improve outcomes with OUD when compared with abstinence treatment alone. Several randomized, controlled, trials showed methadone and buprenorphine were more effective at treating OUD compared with treatment without medication. To date, 3 medications have been FDA-approved for treating OUD: methadone, buprenorphine, and naltrexone.²⁶ All 3 medications differ in their pharmacokinetic and pharmacodynamic profiles and intrinsic activities at central mu-opioid receptor, as summarized in Tables 2-4.^27-31

MethadoneMethadone reduces the euphoric effects of opioid use because it binds to and blocks opioid receptors. Methadone is an opioid replacement strategy; higher dosages are used for maintenance treatment to prevent additional dosages of opioids from causing euphoria. Methadone typically is administered once daily. However, in certain circumstances, such as rapid metabolism or pregnancy, it can be given as a twice-daily dosing regimen. Specific ABCB1 variants and DRD2 genetic polymorphisms (simultaneous occurrence of ≥2 genetically determined phenotypes) might determine the dosage requirements of methadone.³²

Methadone during pregnancy. Methadone is the treatment of choice for opioid-dependent women during pregnancy³³ and is listed as pregnancy category C because it can result in physiologic dependence of the newborn, although there are no documented controlled studies in humans to assess this risk. Methadone can be used while breast-feeding as long as patients are HIV-negative and not abusing other drugs.^34,35 Because the methadone concentration in breast milk generally is low, the medication can be administered to nursing mothers after a careful consideration of risks and benefits.

Methadone administration. There are stringent eligibility criteria for methadone administration; not all physicians are authorized to prescribe methadone. Its use is federally regulated and only licensed treatment programs and licensed inpatient detoxification units can prescribe and dispense methadone in controlled settings and under the direct supervision of clinical personnel (Table 5).³⁶ Patients meeting eligibility criteria can attend a specialized methadone clinic.

One of the challenges when using methadone for long-term management of OUD is tapering the dosage and attempting to discontinue the medication. Discontinuation of methadone leads to withdrawal symptoms and requires a carefully tailored tapering schedule. The literature on methadone tapering is limited. Tapering schedules could differ from practice to practice and, in many cases, are highly individualized based on the need and response of specific patients.

Dosage reduction schedules can last from 2 to 3 weeks to 6 months. Studies indicate rapid reduction worsens treatment outcomes and protracted tapering is associated with better outcomes. A suggested tapering schedule could involve decreasing the dosage by 20% to 25% until reaching a dosage of 30 mg/d, then decreasing by 5 mg/d every 3 to 5 days until reaching a dosage of 10 mg/d, before finally decreasing by 2.5 mg/d every 3 to 5 days.

Some randomized trials have shown better outcomes with long-term treatment. The goal of many programs is transitioning from maintenance treatment to abstinence. However, programs targeting maintenance rather than abstinence have been shown to be more effective.

The FDA has no defined limits for treatment duration with either methadone or buprenorphine. Therefore, the decision to taper or discontinue either medication should be made carefully case by case, using sound clinical judgment. Studies show that methadone treatment could reduce the spread of HIV,^37,38 decrease criminal behaviors,³⁹ and reduce overall mortality rates.⁴⁰ A follow-up study comparing individuals randomly assigned to receive methadone or buprenorphine for OUD showed reduced risk of mortality overall⁴⁰ in both groups.

Adverse events reported during treatment with methadone include decreased libido, erectile dysfunction, constipation, drowsiness, QTc prolongation, and torsade de pointes.⁴¹ Therefore, the FDA recommends obtaining a detailed medical history and baseline electrocardiogram (ECG), with a repeat ECG within the first month of treatment and then annually. Informing patients about the possibility of arrhythmias is part of the informed consent process before starting methadone.

Clinicians also should be vigilant when using methadone in combination with other medications that can prolong the QTc interval (eg, some antipsychotics). Methadone has a greater risk of fatal overdose then buprenorphine. A large-scale study of >16,000 patients reported a 4-fold increase in mortality resulting from methadone overdose compared with buprenorphine.⁴² 

BuprenorphineBuprenorphine is a partial opioid agonist at the mu opioid receptor. A full opioid agonist binds and fully activates the opioid receptors; an antagonist blocks the same. An opioid receptor partial agonist partially activates the receptor. Therefore, an opioid system partial agonist is a functional antagonist and, at lower dosages, has weak agonist effects; at higher dosages, a partial agonist antagonizes other endogenous and exogenous opioids that compete for binding at the same receptor.⁴³ Because of the partial agonist effect, buprenorphine could result in less physical dependence and less withdrawal symptoms.

Administration. In contrast to methadone, buprenorphine can be prescribed by physicians for long-term management of OUD in the United States. Buprenorphine is available in 2 formulations: a sublingual form for daily use and a long-acting form that causes less withdrawal symptoms and cravings. In May 2016 the FDA approved the first buprenorphine implant for use in opioid dependence.^44,45

To prevent withdrawal symptoms, a 24-hour period of opioid abstinence is recommended before starting buprenorphine or buprenorphine/naloxone treatment.⁴⁶ Although lacking empirical evidence, catechol-O-methyltransferase (COMT) inhibitors, such as entacapone, have an anti-craving affect and are used by some clinicians to improve adherence with buprenorphine. This is because of their ability to balance dopamine, which is central to the reward pathway responsible for cravings. Although use of COMT inhibitors might make sense intuitively, such use is off-label and should be based on clinical judgment and a review of the available literature. A study showed that tapering buprenorphine for 4 weeks in combination with naltrexone improved the abstinence rate.⁴⁷

Adverse effects. Some of the adverse events reported during treatment with buprenorphine include fever, back pain, nausea, cough, sedation, difficulty with urination, and constipation. Respiratory depression is a less common effect of buprenorphine, compared with full opioid agonists, because of the medication’s mechanism of action as a partial agonist.⁴⁸ As a result, buprenorphine has been shown to have a lower risk of fatal overdose than methadone.⁴⁹ Studies have shown buprenorphine to be more likely than methadone to reduce neonatal abstinence syndromes.⁵⁰

NaltrexoneNaltrexone is an opioid antagonist and is an option to promote relapse prevention. Because of its antagonist properties, naltrexone treatment should always start after opioid detoxification because it can potentiate immediate withdrawal symptoms. Naltrexone is available in oral and long-acting formulations, the latter of which may be considered in patients who have difficulty with adherence.³⁷

Oral naltrexone is taken as a single 50 mg-tablet once daily, whereas dosing for long-acting naltrexone in injectable and implantable formulations varies. These long-acting naltrexone formulations typically are administered monthly. Some of the adverse events reported during treatment with naltrexone are nausea, liver damage, and injection site pain.⁵¹

Buprenorphine/naloxoneBecause of buprenorphine’s agonist effects, it has a relatively high abuse potential compared with other opioids.⁵² Naloxone, on the other hand, is an opioid antagonist and is poorly absorbed when given orally and is associated with withdrawal symptoms if used intravenously. Therefore, naloxone is added to buprenorphine to decrease the likelihood of abuse when both are used as a combination product.⁵³

Buprenorphine is combined with naloxone in a ratio of 4:1. Induction begins by using a 2 mg/0.5 mg tablet with dosage titration until symptoms abate. A combination of buprenorphine and naloxone also is available in film and tablet formulations. Patients must abstain from other opioids for at least 24 hours before initiating buprenorphine/naloxone treatment to prevent the precipitation of withdrawal symptoms.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.