Topic 3: Pharmacologic Treatment of Underlying Conditions

Underlying attention deficit hyperactivity disorder (ADHD)

ADHD is strongly associated with the development of substance use disorders (SUD), often at a very early age and with a faster transition from less severe to more serious SUD.

In a meta-analysis by H Rohner et al, 2023, which included 29 studies, 23.1% of patients with SUD also had adult ADHD. Patients with benzodiazepine dependence have a higher rate of probable ADHD reaching 31.7% of screened subjects and are more associated with polysubstance abuse (S Effat et al, 2022). 

It is observed that adults with ADHD are often dealing with the symptoms for many years and have developed compensation strategies by misusing substances sometimes that limit the impact and/or mask the symptoms.

Early detection of adult ADHD is of key importance for successful treatment of substance dependence as well.

How it should be approached?

• A detailed history of the onset of symptoms ADHD since childhood and their course since adolescence should be taken in a detailed manner. 
• Then, applying screening tools like Adult ADHD Self-Report Scale (ASRS-SV) screener, Conners’ Adult ADHD Rating Scale, Wender Utah Rating Scale, or Attention Deficit Scales for Adults also allows for good recognition of possible ADHD.
• Evidence– There is a dearth of evidence of specific or evidence-based treatment of ADHD with co-morbid benzodiazepine abuse. Hence, here we will be discussing the general management of adult ADHD.

Studies show that medications are moderately effective in reducing ADHD symptoms in patients with ADHD-SUD comorbidity (mean standardized effect size 0.40–0.50) by M Stuhec et al, 2019.

On the other hand, medication has more positive effects when combined with psychotherapy, while ADHD pharmacotherapy by itself is generally not effective in reducing the use of substances and is associated with a higher frequency of adverse effects and treatment discontinuation.

However, untreated ADHD would lead to the maintenance of problematic behavior.

Stimulant vs Non-stimulants

Several meta-analyses of randomized clinical trials (Koesters 2009; Faraone 2010) and evidence-based guidelines suggest that stimulants should be the first option for treatment for adult ADHD (Nutt 2007).

In a meta-analysis by Mészáros A et al, 2009 which included 11 trials and 1991 adults with ADHD, the pooled effect size for stimulants was somewhat greater versus placebo than for non-stimulant medications (Cohen’s d = 0.67 versus 0.59, respectively).

Another advantage is that onset of the therapeutic effect is immediate in stimulant medication, while atomoxetine and antidepressants have a delayed onset of full therapeutic action of up to four weeks.

Amphetamine

Mechanism of action-Act on the dopamine transporter (DAT) and presumably cause inversion of the transport direction of DAT, resulting in an efflux of dopamine from the presynaptic neuron towards the synapse, gets into the presynaptic neuron through the DAT and causing exocytosis of vesicles containing DA. In addition to increased DA release, amphetamines inhibit catecholamine metabolism through catechol‐O‐methyltransferasse (COMT).

Metabolized in the liver, and the half‐lives are 10 to 15 hours for Mixed Amphetamine Salts and around 12 hours for dexamphetamine (Markowitz 2017).

Evidence- A Cochrane review by Xavier Castells et al, 2018 concluded amphetamines improved the severity of ADHD symptoms. Post hoc sensitivity analysis of clinician-rated symptoms severity of ADHD of amphetamine treatment in adult ADHD was done, the effect size is -0.90 [-1.05, -0.76]. 

Better effect size is noted for Lis-dexamphetamine and mixed amphetamine salts in sensitivity analysis of clinician-related symptom severity of ADHD are 1.04 [-1.19, -0.90] and -0.80 [-0.93, -0.66] respectively.

Medication	Preparation	Onset and DOA	How to prescribe?	Side effects
Dextroamphetamine	Long acting-Dexedrine Spansule	Onset of action-  DOA-6-8 hours	Start at 5 mg per day in the morning, can increase by 5-10 mg per week, maximum dose- 40 mg/day (FDA 2007).	Common side effects- Dry mouth, insomnia, irritability, dysphoria, diminished appetite, weight loss, and headaches, exacerbation of existing motor and vocal tics. Cardiovascular- elevations in systolic and diastolic blood pressure and heart rate  Priapism is a rare complication. Can worsen psychosis
Lis dexamphetamine Pro-drug	Vyvanse	Onset of action- 1 hour DOA- 10 hours	Start at 10/20 mg per day in the morning, can increase by 10 mg per week, maximum dose- 70 mg/day
Dextroamphetamine and amphetamine (mixed salts/MAS)-  contains d‐amphetamine and l‐amphetamine at a ratio of 3:1	Short-acting-Adderall Long acting-Adderall XR	Onset of action-  DOA- 4-6 hours Onset of action-  DOA- 8-12 hours	Start at 5 mg per day in the morning, can increase by 5-10 mg per week, maximum dose- 40 mg/day. (FDA 2015a) Start at 10/20 mg per day in the morning, can increase by 10 mg per week, maximum dose- 60 mg/day

Methylphenidate

Mechanism of action- Methylphenidate works by inhibiting the reuptake of dopamine and norepinephrine, two neurotransmitters involved in regulating attention, impulse control, and executive functions.

Metabolism- After oral administration, methylphenidate is absorbed into the bloodstream primarily from the small intestine, and undergoes significant first-pass metabolism in the liver before reaching the systemic circulation. Metabolism involves enzymatic hydrolysis, primarily by carboxylesterases, to form ritalinic acid as the major metabolite which is inactive. Primarily eliminated through renal excretion (urine) and to a lesser extent through feces.

Evidence- In a meta-analysis of 16 trials including 3799 subjects with ADHD, individuals treated with extended-release methylphenidate showed greater improvements in self-rated ADHD symptoms as compared with placebo (standardized mean difference -0.37, 95% CI -0.43 to 0.3) (Chan et al, 2019). 

Different preparations	Brands	Onset and DOA	How to prescribe?	Side effects
Short-acting	Ritalin, Methylin	Onset- DOA- 2-4 hours	Increase total daily dose by 5 or 10 mg at weekly or greater intervals. Maximum- 60 mg in divided dosage.	Common side effects- Dry mouth, insomnia, irritability, dysphoria, diminished appetite, weight loss, and headaches, exacerbation of existing motor and vocal tics. Cardiovascular- elevations in systolic and diastolic blood pressure (3 to 5 mmHg) and heart rate (five beats per minute) from stimulant treatment of ADHD in adults. these effects do not diminish over time. Risk of arrhythmias etc. Priapism is a rare complication. Can worsen psychosis if has its history, or can precipitate manic symptoms if patient is not under mood stabilizers.
Intermediate-acting	Ritalin SR, Metadate SR	Onset- DOA- 6-8 hours	Increase total daily dose by 5 or 10 mg at weekly or greater intervals. Maximum- 60 mg in morning dose
Long-acting	Ritalin LA, Concerta	Onset- DOA- 8-12 hours	Increase daily dose by 18 mg at weekly or greater intervals (CONCERTA) Once morning dose- maximum-72 mg/day

BUPROPION

Mechanism- Inhibits the reuptake of norepinephrine and dopamine.

Metabolism– Metabolized in the liver. Primarily metabolism is mediated by the cytochrome P450 enzyme CYP2B6. Bupropion is converted into its major active metabolite, hydroxybupropion, through this metabolic pathway. The elimination half-life of bupropion is approximately 21 hours, while the half-life of hydroxybupropion is approximately 20 hours.

Evidence- A Cochrane review by Wim Verbeeck et al, 2017 on bupropion for attention deficit hyperactivity disorder (ADHD) in adults concluded low‐quality evidence that bupropion decreased the severity of ADHD symptoms (standardized mean difference ‐0.50, 95% confidence interval (CI) ‐0.86 to ‐0.15.

In the pharmacological treatment of adults with ADHD, extended‐ or sustained‐release bupropion may be an alternative to stimulants. If a patient has a history of misuse of prescription medication, any contraindications to methylphenidate or amphetamine, co-morbid tobacco dependence, or not tolerate other medications. Then, it can be a good option to use (ASAM, 2023).

Preparation

Onset and duration of action

How to prescribe?

Side- effects

Extended-release (Bupron XL)

Onset- 1-2 weeks
DOA- 12-24 hours depending upon the preparation

Start from 150 mg, after 1 week can increase to 300 mg. Maximum dose- 450 mg/day

Nausea, Vomiting, insomnia, headache, can cause activation- restlessness, agitation, sweating, risk of seizures.

Ques. What should I prefer prescribing between amphetamine and methylphenidate?

Evidence vice- A systematic review and meta-analysis by Matej Stuhec et al, 2018, reported high effect size (expressed as SMD) in reducing ADHD symptoms was observed for Lis dexamphetamine (-0.89; 95% CI = -1.09, -0.70), whereas Mixed amphetamine salts (-0.64; 95% CI = -0.83, -0.45) and MPH (-0.50; 95% CI = -0.58, -0.41) reduced symptoms moderately compared with placebo.

Ques. What to choose between immediate or long-acting preparation?

The type of preparation which is to be prescribed to the patient depends upon the need of the patient, the length of the desired effect for the patient.

However, studies suggest that longer-acting stimulants may be less likely to be abused or diverted due to the slow release of dopamine.

NON-STIMULANTS

ATOMOXETINE

NICE recommends atomoxetine as a second-line medication (or where stimulants are contraindicated).

It is a Nor-epinephrine re-uptake inhibitor.

Metabolism- well-absorbed from the gastrointestinal tract, metabolized in the liver by various enzymes mainly CyP2D6, and CyP 3A4. One of the metabolites of atomoxetine, known as 4-hydroxy atomoxetine (O-desmethyl atomoxetine), is pharmacologically active and contributes to the overall therapeutic effects of the medication. Primarily eliminated through renal excretion (urine).

Evidence- A meta-analysis of 13 controlled trials by Vinutha Ravishankar et al, 2016 for assessing the efficacy of atomoxetine in treating adult attention deficit hyperactivity disorder (ADHD) reported that atomoxetine had superior efficacy to placebo on overall adult ADHD scores [-0.45; 95% CI -0.54, -0.35; overall effect p<0.00001]. It was superior to placebo on the domains of both inattention [-0.42; 95% CI -0.49, -0.35; overall effect p<0.00001] and impulsivity/hyperactivity [-0.36; 95% CI -0.44, -0.29; overall effect p<0.00001].

Atomoxetine has little to no abuse potential and can be used safely used in patients with substance use disorder.

Should not be used in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to its noradrenergic effects.

The onset of action- Atomoxetine’s onset of action is gradual, and it may take several weeks, the maximum benefit is usually achieved after about 4 to 6 weeks of consistent use. Duration of action- Once the medication reaches its therapeutic effect, it typically provides symptom control throughout the day.	How to prescribe? Starting dosage for those who weigh up to 70kg is 0.5mg/kg daily and the maximum dosage is 1.8mg/kg daily (120mg daily).  For those who weigh over 70kg, start at a dosage of 40mg daily up to a maximum of 120mg daily	Side effects Dry mouth, insomnia, nausea, decreased appetite, constipation. Decreased libido, erectile dysfunction, urinary hesitancy, Dizziness, and sweating; QTc prolongation. Aggressive behavior or hostility, and the emergence of psychosis or mania
TRICYCLIC ANTI-DEPRESSANTS	The certainty of evidence evaluated by the GRADE approach varied from very low to low, due to methodological limitations of RCTs, small sample size, wide confidence interval, and heterogeneity between included studies (Giovanna Marcílio Santos et al, 2021). Benefits of TCAs treatment include their effectiveness in treating co-occurring depression or anxiety with ADHD, and tic disorder plus lack of abuse liability, and single daily dosing. Risks of cardiotoxicity, particularly with overdose, should prompt careful monitoring of TCA treatment.

Other medications like Modafinil, clonidine, and guanfacine don’t have much evidence in Adult ADHD.

UNDERLYING CHRONIC INSOMNIA

Cognitive behavioral therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). 

A pharmacological intervention can be offered if cognitive behavioral therapy for insomnia is not sufficiently effective or not available.

Antidepressants

Routine use of sedating antidepressants other than low-dose doxepin is not recommended to treat insomnia in patients who are not depressed because the sedating effect tends to be short-lived and other side effects are common

Mirtazapine
(Most common off-label prescriptions for insomnia)

Receptors implicated in sedative action– H1 antagonist, 5HT2A antagonism (enhances slow-wave sleep), 5HT2C antagonist.
Elimination half-life in the range of 20 to 40 hours
Side effects-Somnolence, increased appetite, weight gain, dizziness, impairment in judgment, thinking, and motor skills
Dosage- 7.5-15 mg/day, at higher doses it can be activating

Off- label treatments for insomnia

Trazodone
(Most common off-label prescriptions for insomnia)

Receptors implicated in sedative action– H1 antagonist, 5HT2A antagonism (enhances slow-wave sleep), 5HT2C antagonist, α1 blocker. 

Reduce arousal in insomnia rather than by enhancing sleep drive.
Elimination half-life of approximately 5-9 hours
Side effects-Syncope, edema, blurred vision, diarrhea, nasal congestion, and weight loss, priapism, urinary incontinence, QTc prolongation
Advantage– not been associated with tolerance, withdrawal, dependence, or rebound.
Dosage-25-150 mg/day

Off- label treatments for insomnia

Amitriptyline
(Most common off-label prescriptions for insomnia)

Receptors implicated in sedative action- H1 antagonist, Muscarinic antagonist, Alpha- antagonist,
Side effects- somnolence, weight gain, dry mouth, constipation, dizziness, headache, orthostatic hypotension, falls, risk of seizures.
Dosage– 10-50 mg/day

Off- label treatments for insomnia

Doxepin (TCA)

Receptors implicated in sedative action – H1 antagonist (very high affinity), Muscarinic antagonist, 
Side effects- sedation, headache, dry mouth, constipation, dizziness, confusion, memory changes.

Treatment for sleep maintenance insomnia in adults. 

Dosage-3-6 mg/day  (taken 30 minutes before bed time)

A systematic review by Yeung WF et al, 2015, included 9 RCTs reported low-dose doxepin provided modest improvements in sleep maintenance and sleep duration but had no effect on sleep initiation.

BENZODIAZEPINE RECEPTOR AGONIST

Receptors implicated in sedative action -GABA-A Positive Allosteric Modulators. Zaleplon and Zolpidem binds selectively to α1 subunits of benzodiazepine-sensitive GABAA receptors, may contribute to lower risk of tolerance and dependence. 

However, they also have potential for dependence. Metabolized by Cyp3A4.

Side effects- amnesia, dizziness, sedation, headache, nausea, and taste perversion (altered or unpleasant taste).The US Food and Drug Administration (FDA) added a boxed warning in 2019 on the risk of rare but serious complex sleep-related behaviours.

Zolpidem

Use zolpidem as a treatment for sleep onset and sleep maintenance insomnia in adults.
 Half-life- approximately 1.5 to 4.5 hours 
Dosage- 5-20 mg/day

Weak evidence
(GRADE) * (Franco De Crescenzo et al, 2022)

Zaleplon

As a treatment for sleep onset insomnia in adults.
Half-life- Shortest (approximately 1-2 hours). The absorption of zaleplon is delayed by approximately two hours and is reduced by 35% if the drug is taken with high-fat or heavy meals.
Dosage- 5-20 mg/day
Headache and dizziness were the most common adverse events in clinical studies of zaleplon.

Weak evidence
(GRADE) * (Franco De Crescenzo et al, 2022)

Eszopiclone

Eszopiclone is the active isomer of zopiclone but binds preferentially to the α-3 benzodiazepine GABA receptor subtype, which might underpin its particular therapeutic profile.
As a treatment for sleep onset and sleep maintenance insomnia in adults.
Half-life- Longest (approximately 6 hours)
Dosage- 1-3 mg/day
Side effects- common- unpleasant taste, headache, somnolence, and dizziness
In May 2014, the FDA issued a warning regarding next-day impairment of driving and other activities after the use of eszopiclone.

More effective than placebo- SMD 0·63 [95% CI
0·36–0·90; very low] * (Franco De Crescenzo et al, 2022)

OREXIN RECEPTOR AGONIST

Mechanism of action- The orexin system promotes and stabilizes wakefulness with projections from the hypothalamus to the cortex and to the nuclei of multiple wake-promoting neurotransmitters (histamine, acetylcholine, dopamine, serotonin, and norepinephrine). 

Orexin neurotransmission is mediated by two types of postsynaptic G-protein-coupled receptors, orexin 1 (OX1R) and orexin 2 (OX2R) and block the wake-stabilizing effects of the orexins. They are reversible inhibitors.

OX1R are particularly expressed in the noradrenergic locus coeruleus.

OX2R are highly expressed in the histaminergic tuberomammillary nucleus (TMN). Blockade of orexin receptors by dual orexin receptor antagonists (DORAs) prevents the excitatory effects of orexin neurotransmitters.

Advantage- lacks dependence, withdrawal, rebound, unsteady gait, falls, confusion, amnesia, or respiratory depression.

Disadvantage- High cost, a recent meal may delay the onset of action

Side effects- Somnolence, sleep paralysis, hypnagogic or hypnopompic hallucinations, and cataplexy-like symptoms. Contraindicated in narcolepsy.

Lemborexant

It has higher affinity for OX2R than for OX1R. 
In treatment for both sleep onset and maintenance insomnia in adults. 
Half-life- Longest (approximately 17-19 hours)
Dosage- Start with 5 mg, immediately before bedtime depending upon response and tolerability- can increase to 10 mg/day

More effective than placebo- SMD-0·41 [0·04–0·78; very low]) * (Franco De Crescenzo et al, 2022)

Suvorexant

It has comparable affinity for orexin 1 (OX1R) and orexin 2 (OX2R) receptors. 
 In treatment for both sleep onset and maintenance insomnia in adults. 
Dosage– Start with 10 mg, 30 minutes before bedtime depending upon response and tolerability- can increase to 20 mg/day

Weak evidence
(GRADE) * (Franco De Crescenzo et al, 2022)

Melatonin agonist

Mechanism of action- Melatonin shifts circadian rhythms, especially in those with phase delay when taken at the desired appropriate bedtime

Side effects- Somnolence, dizziness, fatigue, nausea, and exacerbation of insomnia.

Ramalteon

MT1/MT2 agonist marketed for insomnia, treatment for circadian rhythm disorders in adults.

Ramelteon facilitates sleep onset by decreasing the typical evening SCN-driven arousal (MT1), and helps to reinforce circadian periodicity (MT2).  Elimination half-life approximately 1 to 2.6 hours.

Dosage-8-16 mg/day. Avoid taking with or soon after a high-fat meal.

Most common ramelteon-related adverse events include dizziness, nausea, and fatigue

SMD (0.63 [0·16–1·10; very low]); Weak evidence (GRADE) * (Franco De Crescenzo et al, 2022)

Anti-psychotics

Receptors mediating sedative action- H1 antagonist, Anti-cholinergic, Anti-muscarinic action

Side effects- Generally, not recommended to use because of their side effects.

Quetiapine (Most common off-label prescriptions for insomnia)	Dosage-25-100 mg/day	Because of insufficient evidence and in light of their side-effects, antipsychotics are not recommended for (very low-quality evidence) *insomnia treatment  Dieter Riemann et al, 2017
Chlorpromazine (Most common off-label prescriptions for insomnia)	Dosage-25-100 mg/day

Anti-histaminics

Receptors mediating sedative action- H1 antagonist mainly mediates sedation. Postsynaptic muscarinic antagonism may cause undesired anticholinergic effects

Side effects- sedation, dizziness, disturbed coordination, epigastric distress, and thickening of bronchial secretions.

Potential for rapid tolerance, studies have indicated that diphenhydramine and doxylamine are only minimally effective in inducing sleep, may reduce sleep quality, and may cause residual drowsiness (Richardson GS et al, 2002)

Diphenhydramine	Half-life of diphenhydramine is 9 to 10 hours. Dosage-25- 50 mg/day	Because of insufficient evidence, anti-histaminics are not recommended for insomnia treatment (strong recommendation, low-quality evidence) * Dieter Riemann et al, 2017
Doxylamine	Half-life of diphenhydramine is 10 to 12 hours. Dosage-25-50 mg/day

UNDERLYING ANXIETY AND MOOD CONDITIONS

Both anxiety and substance use disorders have common neurotransmitter systems that are implicated in their aetiology. The neurotransmitter systems include the GABAergic, serotonergic, noradrenergic, and excitatory amino acid systems.

Reasons of benzodiazepine dependence in anxiety disorders-

• • Immediate Symptom Relief- This rapid relief can lead individuals with anxiety disorders to rely on benzodiazepines as a quick and accessible solution for their distressing symptoms.
  • Perceived Effectiveness: Benzodiazepines are initially effective in reducing anxiety symptoms, which reinforces the belief that they are an effective long-term solution.
  • Lack of Alternative Coping Strategies
• • Tolerance and Dependence: With prolonged use, tolerance to the anxiolytic effects of benzodiazepines can develop. This may lead individuals to increase their dosage or frequency of use to achieve the desired effect. 
  • Fear of Withdrawal
  • Lack of Awareness or Education: Some individuals with anxiety disorders may not be fully aware of the potential risks and long-term consequences of benzodiazepine use.

PHARMACOLOGICAL MANAGEMENT

It’s essential to address above mentioned factors (reasons of taking benzodiazepines), when managing benzodiazepine use in individuals with anxiety disorders. 

Obtaining an accurate longitudinal history with particular attention to the onset of both disorders.

The optimal strategy in which to differentiate substance-induced from primary anxiety disorders is through observation of anxiety symptoms over a period of abstinence. substance-induced anxiety symptoms will resolve two to four weeks after last substance use.

The observation of symptoms over time must also take into account the severity of symptoms so as not to withhold treatment if warranted.

On the other hand, primary anxiety disorders will usually have increased severity after cessation of substance use whereas substance-induced anxiety symptoms slowly remit after cessation of substance use.

Controlled trials in patients with comorbid substance use disorders and anxiety disorders have not been reported.

The ideal approach to the pharmacological treatment of these comorbid conditions would be to use an agent that has no abuse potential, is safe and well-tolerated, and may be efficacious in both disorders.

Selective serotonin reuptake inhibitors
(SSRIs)

For anxiety disorders, SSRIs are typically considered first-line psychopharmacological agents for the treatment of anxiety disorders.
Start with a low dose of medication in order to avoid activation that may increase the patient’s anxiety and therefore increase the risk for relapse.
Social phobia- sertraline, paroxetine, and venlafaxine.
Sertraline and Paroxetine have FDA indications for the treatment of panic disorder.
Venlafaxine, a serotonin/norepinephrine reuptake inhibitor, and Paroxetine have a FDA indication for the treatment of GAD.
All SSRIs are approved by FDA including escitalopram, sertraline, paroxetine, fluoxetine, fluvoxamine for OCD.
Common side effects- Git side effects- nausea, vomiting, diarrhoea, constipation, Sexual side effects, sleep disturbances, weight changes, headache, dry mouth, dizziness.

Tri-cyclic anti-depressants
(TCAs)

TCAs are also effective in managing anxiety and certain mood disorders, may be considered for individuals with treatment-resistant depression, meaning they have not responded adequately to other antidepressant medications.
Common side effects of TCAs include dry mouth, constipation, blurred vision, urinary retention, drowsiness, weight gain, and potential cardiac effects. TCAs also have a higher risk of overdose and may require careful monitoring, especially in individuals with certain medical conditions.
Issues– poorly tolerated by some individuals and have drug-to-drug interactions that can be particularly worrisome in alcohol and cocaine-dependent patients, lethality of TCAs in overdose and the dose-related lowering of the seizure threshold.

Buspirone Serotonin partial agonist

Non-benzodiazepine anxiolytic thought to act as a partial 5-HT1A agonist. 
Buspirone has been found to be as effective as benzodiazepines in the treatment of GAD, but without the abuse potential.
Side effects- Dizziness or light-headedness, headache, restlessness, Nausea or upset stomach, Drowsiness or fatigue, dry mouth, rarely muscle aches