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Psychostimulants

      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. The content is also available on www.palliativedrugs.com and will feature in future editions of the Hospice and Palliative Care Formulary USA and its British and Canadian counterparts. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      Off-label indication
      CYP
      Cytochrome P450
      D1, D2
      Dopamine-1, Dopamine-2 receptors
      GABA
      Gamma-aminobutyric acid
      INR
      International normalized ratio
      RCT
      Randomized controlled trial
      Indications: Licensed indications vary between products; consult Prescribing Information for details. Attention deficit hyperactivity disorder; daytime drowsiness due to narcolepsy, obstructive sleep apnea or chronic shift work-related sleep disorder; †depression when prognosis <3 months; †opioid-related drowsiness; †fatigue refractory to correction of underlying contributory factors.
      Contraindications: Amphetamines and other psychostimulants should not be prescribed concurrently or within 14 days of the use of a monoamine oxidase inhibitor (MAOI) because of the risk of precipitating a hypertensive crisis (characterized by severe hypertension, headache and hyperpyrexia). Psychostimulants also should not be used in patients receiving procarbazine (an antineoplastic drug) because this is a weak MAOI.

      Pharmacology

      Psychostimulants increase alertness and motivation, and have antidepressant and mood-elevating properties.
      • Kumar R.
      Approved and investigational uses of modafinil: an evidence-based review.
      • Boutrel B.
      • Koob G.F.
      What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.
      • Qu W.M.
      • Huang Z.L.
      • Xu X.H.
      • Matsumoto N.
      • Urade Y.
      Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.
      • Volkow N.D.
      • Fowler J.S.
      • Logan J.
      • et al.
      Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.
      This drug class includes combined dextroamphetamine/amphetamine salts, lisdexamfetamine, dexmethylphenidate, and armodafinil. However, this review will focus on dextroamphetamine, methylphenidate, and modafinil, which have the best evidence base to support use in palliative care.
      • Candy M.
      • Jones L.
      • Williams R.
      • Tookman A.
      • King M.
      Psychostimulants for depression.
      Further, the newer alternatives are generally significantly more expensive, and have no proven additional pharmacological benefit.
      Caffeine is a time-honored traditional psychostimulant widely used in the community. It is an adenosine type-1 receptor antagonist. It blocks the sleep-promoting GABAergic and antidopaminergic effects of adenosine, which accumulates during wakefulness.
      • Boutrel B.
      • Koob G.F.
      What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.
      However, medicinal psychostimulants are used when traditional measures are inadequate.
      Although the specific mechanisms of action may vary, medicinal psychostimulants generally appear to act directly or indirectly via dopamine.
      • Boutrel B.
      • Koob G.F.
      What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.
      • Qu W.M.
      • Huang Z.L.
      • Xu X.H.
      • Matsumoto N.
      • Urade Y.
      Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.
      • Volkow N.D.
      • Fowler J.S.
      • Logan J.
      • et al.
      Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications.
      • Fleckenstein A.E.
      • Volz T.J.
      • Riddle E.L.
      • Gibb J.W.
      • Hanson G.R.
      New insights into the mechanism of action of amphetamines.
      • Sulzer D.
      • Sonders M.S.
      • Poulsen N.W.
      • Galli A.
      Mechanisms of neurotransmitter release by amphetamines: a review.
      Dopamine has an important role in the mesolimbic and mesocortical systems, which are concerned with reward, motivation, attention, and arousal. It is released in response to relevant stimuli and thoughts, particularly those associated with reward. These effects are mediated by D1 and D2 receptors.
      • Boutrel B.
      • Koob G.F.
      What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.
      • Kapur S.
      • Mizrahi R.
      • Li M.
      From dopamine to salience to psychosis–linking biology, pharmacology and phenomenology of psychosis.
      Dopaminergic dysfunction in the mesolimbic and mesocortical systems is implicated in several disorders. In attention-deficit hyperactivity disorder, psychostimulants may improve attention by correcting a deficit in dopamine release in response to relevant stimuli.
      • Volkow N.D.
      • Wang G.J.
      • Fowler J.S.
      • Ding Y.S.
      Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder.
      Conversely, in psychoses, dopamine excess (“over-attention”) may cause hallucinations and delusions, and may account for the beneficial effects of D2 antagonists.
      • Kapur S.
      • Mizrahi R.
      • Li M.
      From dopamine to salience to psychosis–linking biology, pharmacology and phenomenology of psychosis.
      There is also interest in inhibiting dopamine-mediated “reward” systems in addiction disorders.
      Methylphenidate is probably the most widely used psychostimulant in palliative care.
      • Dein S.
      • George R.
      A place for psychostimulants in palliative care?.
      • Masand P.S.
      • Tesar G.E.
      Use of stimulants in the medically ill.
      However, dextroamphetamine has a potential advantage because it is more often effective with once daily dosing.
      • Burns M.M.
      • Eisendrath S.J.
      Dextroamphetamine treatment for depression in terminally ill patients.
      Sustained-release preparations, though more expensive, may be worth the extra cost if the convenience of prolonged duration of effect without repeat administration is desired. Sustained-release preparations also have more risk of insomnia, particularly if taken later in the day.
      About half or less of a dose of dextroamphetamine is excreted renally and largely unchanged; there is thus a theoretical risk of increased toxicity in renal impairment.
      • Dein S.
      • George R.
      A place for psychostimulants in palliative care?.
      For selected pharmacokinetic data, see Table 1.
      Table 1Pharmacokinetic Details for Selected Psychostimulants
      • Challman T.D.
      • Lipsky J.J.
      Methylphenidate: its pharmacology and uses.
      • de la Torre R.
      • Farré M.
      • Navarro M.
      • et al.
      Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices.
      • Connor D.F.
      • Steingard R.J.
      New formulations of stimulants for attention-deficit hyperactivity disorder: therapeutic potential.
      • Robertson Jr., P.
      • Hellriegel E.T.
      Clinical pharmacokinetic profile of modafinil.
      Oral Bio-availability (%)Time to Peak Plasma Concentration (h)Half-Life (h)Metabolism
      DextroamphetamineNo data2–47–17Multiple routes; ≤50% renally excreted unchanged
      Methylphenidate30
      Almost completely absorbed but undergoes extensive first pass hepatic metabolism.
      1–32Non-CYP carboxylesterase
      Metabolites are inactive.
      Modafinil≥401.5–3d-modafinil 3;

       l-modafinil 10–16
      CYP3A4; non-CYP esterase
      Metabolites are inactive.
      a Almost completely absorbed but undergoes extensive first pass hepatic metabolism.
      b Metabolites are inactive.

      Cautions

      For full list, see manufacturers’ Prescribing Information.
      Psychostimulants may exacerbate cardiovascular disease (e.g., severe hypertension, arrhythmia, and angina); psychiatric illness (e.g., anxiety, agitation, psychosis, and addiction disorders); epilepsy (possible lowering of seizure threshold); hyperthyroidism and closed-angle glaucoma (not modafinil).

      Drug Interactions

      For full list, see manufacturers’ Prescribing Information.
      Pharmacodynamic interactions include those with sympathomimetics (e.g., MAOI, see contra-indications) and antipsychotics (reduced stimulant effect).
      Methylphenidate and modafinil may increase plasma concentrations of tricyclic antidepressants, phenytoin, and warfarin (check INR at least weekly until stabilized). Modafinil also may increase the plasma concentrations of diazepam.
      Modafinil induces CYP3A4/5 (reduced efficacy of cyclosporine, HIV-protease inhibitors, midazolam, calcium channel blockers, statins, and hormonal contraception). Modafinil also inhibits CYP2C19 and thus may decrease the plasma concentrations of the active metabolites of clopidogrel.

      Undesirable Effects

      For full list, see manufacturers’ Prescribing Information.
      Undesirable effects have been reported in up to 30% of patients.
      Neuropsychiatric: insomnia, agitation, and anorexia (generally settle after 2–3 weeks if the drug is continued or resolve after 2–3 days if the drug is discontinued), psychosis, movement disorders.
      Cardiovascular: tachyarrhythmias, hypertension, and angina (rare).
      Other: headache, common and responds to slower dose titration; very rarely cerebral arteritis occurs with methylphenidate. Mild rashes are common with modafinil; serious skin reactions occur in 1% of children.

      Use of Psychostimulants in Palliative Care

      A psychostimulant is probably prescribed to less than 5–10% of patients receiving palliative care. Consider warning patients about possible jitteriness, anxiety, insomnia, and/or anorexia.

      Depression

      Psychostimulants are used where a prompt response to treatment is required and tolerance to long-term use is irrelevant. A consensus panel concluded that they were the drugs of choice for treating depression in patients with a prognosis of <3 months.
      • Block S.
      Assessing and managing depression in the terminally ill patient.
      If daily review is practical, it is often possible to achieve a response in a few days, increasing the dose every 1–2 days until a response is obtained or undesirable effects prevent further escalation (Box 1).
      • Masand P.S.
      • Tesar G.E.
      Use of stimulants in the medically ill.
      • Block S.
      Assessing and managing depression in the terminally ill patient.
      However, published trials are generally of poor quality, short duration, and with outcome measures of uncertain clinical significance. Thus, conventional antidepressants are the drugs of choice for a patient with a sufficient prognosis for a response to manifest, e.g., ≥2–3 months.
      • Candy M.
      • Jones L.
      • Williams R.
      • Tookman A.
      • King M.
      Psychostimulants for depression.
      • Block S.
      Assessing and managing depression in the terminally ill patient.
      • Orr K.
      • Taylor D.
      Psychostimulants in the treatment of depression: a review of the evidence.
      Concurrent use with a conventional antidepressant has been reported, and may hasten the response compared with the latter alone, particularly in relation to fatigue.
      • Orr K.
      • Taylor D.
      Psychostimulants in the treatment of depression: a review of the evidence.
      Guidelines used at some centers for psychostimulants in depressed patients
      A psychostimulant is the drug of choice for treating depression in patients with a prognosis of <3 months because they may not live long enough to benefit maximally from a conventional antidepressant. It is often possible to achieve a response in a few days by increasing the dose progressively until benefit or undesirable effects occur. Psychostimulants are generally considered not as effective as conventional antidepressants, and these should be considered instead or concurrently in patients with a sufficient prognosis for a response to manifest, e.g., ≥2–3 months.
      Advantages
      Well tolerated and generally effective.
      No lag time to effect.
      Rapid clearance from the body.
      Paradoxically improve appetite in the physically ill.
      Disadvantages
      Can only be given by mouth.
      May precipitate/exacerbate delirium.
      Undesirable effects include restlessness, hallucinations, insomnia, tachycardia, hypertension.
      Tolerance may develop.
      Withdrawal depression if stopped abruptly after prolonged use.
      Management strategy
      Start with recommended doses (see below).
      Re-assess after 2–3 hours to observe maximum benefit and undesirable effects.
      Because of the rapid onset of effect, adjust the dose every 1–2 days by the smallest practical amount until:
      • the depression resolves or
      • unacceptable undesirable effects occur or
      • the maximum recommended dose is reached.
      Drugs of choice
      Methylphenidate:
      • start with 2.5–5 mg b.i.d. (early morning and noon)
      • if necessary, increase progressively every 1–2 days to 20 mg b.i.d.
      Dextroamphetamine:
      • start with 2.5–5 mg each morning
      • if necessary, increase progressively every 1–2 days to 20 mg each morning
      • some patients may require b.i.d. dosing (early morning and noon) if the effect wears off too quickly.
      Modafinil:
      • start with 100 mg each morning
      • if necessary, increase to 200 mg each morning after 1–2 days
      • doses up to 400 mg have been used.
      Methylphenidate is probably the most commonly used psychostimulant for depression in palliative care. With cautious dosing and attention to response, psychostimulants are generally well tolerated (Box 1). Although undesirable effects are similar for all psychostimulants, some patients benefit by switching to an alternative if the first choice is ineffective or poorly tolerated.

      Fatigue

      Psychostimulants may be considered for the treatment of fatigue when other approaches are insufficient.
      • Radbruch L.
      • Strasser F.
      • Elsner F.
      • et al.
      Fatigue in palliative care patients – an EAPC approach.
      • Minton O.
      • Richardson A.
      • Sharpe M.
      • Hotopf M.
      • Stone P.
      A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue.
      • National Comprehensive Cancer Network (NCCN)
      NCCN clinical practice guidelines in oncology: cancer-related fatigue.
      These include, when feasible, the correction of underlying causal factors (e.g., anemia, depression, and electrolyte disturbance) and modification to the patient’s daily routine (e.g., gentle exercise, energy conservation, and practical help to aid adjustment to changing circumstances).
      • Radbruch L.
      • Strasser F.
      • Elsner F.
      • et al.
      Fatigue in palliative care patients – an EAPC approach.
      However, RCTs yield conflicting results and the routine use of psychostimulants for fatigue remains controversial.
      In cancer patients, methylphenidate
      • Bruera E.
      • Valero V.
      • Driver L.
      • et al.
      Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial.
      and dextroamphetamine
      • Auret K.A.
      • Schug S.A.
      • Bremner A.P.
      • Bulsara M.
      A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer.
      were ineffective for cancer-related fatigue, although results of trials of dexmethylphenidate for chemotherapy-related fatigue were conflicting.
      • Mar Fan H.G.
      • Clemons M.
      • Xu W.
      • et al.
      A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer.
      • Lower E.E.
      • Fleishman S.
      • Cooper A.
      • et al.
      Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial.
      A single-dose study found modafinil improved drowsiness, psychomotor speed and attention in patients with advanced cancer.
      • Lundorff L.E.
      • Jønsson B.H.
      • Sjøgren P.
      Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial.
      Further trials of modafinil in cancer patients are underway.
      RCTs examining modafinil for fatigue in myotonic dystrophy, Parkinson’s disease, and traumatic brain injury found little or no effect.
      • Kumar R.
      Approved and investigational uses of modafinil: an evidence-based review.
      • Lou J.S.
      • Dimitrova D.M.
      • Park B.S.
      • et al.
      Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study.
      Fatigue in multiple sclerosis improved in a small cross-over RCT
      • Lange R.
      • Volkmer M.
      • Heesen C.
      • Liepert J.
      Modafinil effects in multiple sclerosis patients with fatigue.
      but not in a larger parallel group study.
      • Stankoff B.
      • Waubant E.
      • Confavreux C.
      • et al.
      Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study.
      Benefit was shown in amyotrophic lateral sclerosis (motor neuron disease).
      • Rabkin J.G.
      • Gordon P.H.
      • McElhiney M.
      • et al.
      Modafinil treatment of fatigue in patients with ALS: a placebo-controlled study.
      A lack of clear benefit may relate, in part, to the large placebo response seen in many trials. Further, some have suggested that the b.i.d. drug regimen may have interfered with sleep and thus exacerbated fatigue in some patients.
      • Rammohan K.W.
      • Lynn D.J.
      Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study.

      Opioid-Related Drowsiness

      Drowsiness is common when opioids are commenced or the dose is increased; it is generally transient. Persistent drowsiness may indicate opioid toxicity; a trial dose reduction should be made and other drug and non-drug approaches considered to provide adequate analgesia.
      • Twycross R.
      • Wilcock A.
      Adjuvant analgesics.
      However, some patients experience persistent drowsiness despite adjusting the opioid dose. In this circumstance, switching to an alternative opioid may be of benefit.
      • Twycross R.
      • Wilcock A.
      Opioid dose conversion ratios.
      Psychostimulants are sometimes used for opioid-related drowsiness refractory to these measures. They improve psychomotor performance and allow opioid dose escalation to a higher level than would otherwise be possible.
      • Dalal S.
      • Melzack R.
      Potentiation of opioid analgesia by psychostimulant drugs: a review.
      This can be particularly helpful for patients experiencing break-through (episodic) pain.
      • Bruera E.
      • Brenneis C.
      • Paterson A.H.
      • MacDonald R.N.
      Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer.
      • Wilwerding M.B.
      • Loprinzi C.L.
      • Mailliard J.A.
      • et al.
      A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics.
      • Bruera E.
      • Fainsinger R.
      • MacEachern T.
      • Hanson J.
      The use of methylphenidate in patients with incident cancer pain receiving regular opiates: a preliminary report.
      • Bruera E.
      • Miller M.J.
      • Macmillan K.
      • Kuehn N.
      Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain.

      Supply

      Psychostimulants are controlled substances in the USA. Amphetamines and methylphenidate are Schedule II and modafinil Schedule IV. Sustained-release formulations are available for some stimulants (see below).
      Dextroamphetamine (generic)
      Tablets 5 mg, 10 mg, 28 days @ 10 mg once daily=$50.
      Methylphenidate (generic)
      Tablets 5 mg, 10 mg, 20 mg, 28 days @ 10 mg b.i.d.=$23.
      Methylin® (Mallinckrodt)
      Tablets 5 mg, 10 mg, 20 mg, 28 days @ 10 mg b.i.d.=$23.
      Tablets chewable 2.5 mg, 5 mg, 10 mg, 28 days @ 10 mg b.i.d.=$58.
      Oral solution 1 mg/mL, 5 mg/mL, 28 days @ 10 mg b.i.d.=$27.
      Ritalin® (Novartis)
      Tablets 5 mg, 10 mg, 20 mg, 28 days @ 10 mg b.i.d.=$51.
      Sustained-release
      Concerta® (Ortho-McNeil-Janssen)
      Tablets 18 mg, 27 mg, 36 mg, 54 mg, 28 days @ 36 mg once daily=$142.
      Metadate® CD (UCB)
      Capsules 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 28 days @ 20 mg once daily=$109.
      Daytrana® (Shire)
      Transdermal patch 10 mg, 15 mg, 20 mg, 30 mg, 28 days @ 20 mg once daily=$151.
      Modafinil
      Provigil® (Cephalon)
      Tablets 100 mg, 200 mg, 28 days @ 200 mg once daily=$80.

      Other Psychostimulants

      Armodafinil
      Nuvigil® (Cephalon)
      Tablets 50 mg, 150 mg, 250 mg, 28 days @ 150 mg once daily=$293.
      Dexmethylphenidate
      Focalin® (Novartis)
      Tablets 2.5 mg, 5 mg, 10 mg, 28 days @ 5 mg b.i.d.=$54.
      Sustained-release
      Focalin XR® (Novartis)
      Capsules 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 28 days @ 10 mg once daily=$133.
      Dextroamphetamine/amphetamine salts
      Adderall® (Shire)
      Tablets 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg, 28 days @ 10 mg b.i.d.=$190.
      Sustained-release
      Adderall XR® (Shire)
      Capsules 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 28 days @ 20 mg once daily =$218.
      Lisdexamfetamine
      Vyvanse® (Shire)
      Capsules 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 28 days @ 50 mg once daily=$135.
      This is not a complete list.

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