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Psychostimulants: new concepts for palliative care from the modafinil experience?

      To the Editor:
      Recent advances in the pathophysiology of wakefulness
      • Pace-Schott E.F
      • Hobson J.A
      Basic mechanisms of sleep: new evidence on the neuroanatomy and neuromodulation of the NREM-REM cycle.
      can provide useful insight in clinical situations not rarely found in palliative care. We wanted to summarize briefly some aspects of this area of pharmacological research and to present two clinical cases to foster discussion in the field.
      Sleepiness, reduced level of consciousness, or sedation are commonly seen in palliative care. These terms are used in different situations. Sleepiness may describe normal or excessive, subjective or objective, reduction of daily wakefulness. Sedation may be a side effect of drugs, and reduced level of consciousness often is noted as a sign of structural or functional brain damage.
      Specific neuroanatomical areas are regulating level of consciousness and the sleep-wakefulness cycle, and are deemed responsible for physiological and pathological conditions, ranging from insomnia to delirium, from hypersomnia to coma. The relative contribution of the cholinergic, adrenergic, serotonergic, histaminergic, and gabaergic pathways in these brain areas to the maintenance of normal wakefulness and circadian sleep-wakefulness rhythm is complex. Among the cerebral structures involved in this system are the reticular formation of the brainstem (ascending activating reticular system, ARAS), the medial and reticular thalamic nuclei, the hypothalamus, and the projections from these areas to the cortical mantle modulating cerebral arousal and level of consciousness (Table 1).
      • Pace-Schott E.F
      • Hobson J.A
      Basic mechanisms of sleep: new evidence on the neuroanatomy and neuromodulation of the NREM-REM cycle.
      Table 1Brain Centers and Neurotransmitters Active in Maintaining and Modulating Normal Wakefulness and Level of Consciousness
      Brain Structures Active During AwakingNeurotransmitterConnections with Other Centers and Effects
      Pons dorsal raphe nucleusSerotoninEntire forebrain activation
      Cortical modulation
      Pons locus coeruleusNorepinephrineEntire forebrain activation
      Cortical modulation
      Midbrain substatia nigra and ventral tegmental areaDopamineEntire forebrain activation and cortical modulation
      Pons laterodorsal tegmental and peduncolopontine nucleiAcetylcholineDiencephalon (thalamus and hypothalamus)
      Basal forebrain magnocellular cellsAcetylcholineLimbic forebrain
      Nucleus basalis of MeynertAcetylcholineCortex
      Posterior hypothalamus (tuberomammillary nucleus)HistaminePromoting arousal systems of entire forebrain and brainstem (listed above)
      Active also at thalamic, limbic, and cortical level
      Lateral hypothalamusOrexin (Hypocretin)Promoting arousal systems of entire forebrain and brainstem (listed above)
      Active also at thalamic, limbic, and cortical level
      Hypothalamic inhibitory areasGamma aminobutyric acid (GABA)Reciprocal inhibition of hypothalamic areas promoting sleep
      One crucial crossroad in this system is the hypothalamus, which promotes sleep with its anterior preoptic nuclei and awakening with its posterior and lateral areas.
      • Pace-Schott E.F
      • Hobson J.A
      Basic mechanisms of sleep: new evidence on the neuroanatomy and neuromodulation of the NREM-REM cycle.
      A novel neurotransmitter, hypocretin 1 (also named orexin A), has been identified in the lateral hypothalamus. Hypocretin-mediated projections can be found from the hypothalamus to the monoaminergic and cholinergic components of the ascending reticular activating system (Table 1).
      • Silber M.H
      • Rye D.B
      Solving the mystery of narcolepsy. The hypocretin story.
      The link between hypocretin and different pathological changes of wakefulness in patients is affirmed by the observation that CSF hypocretin is practically absent in narcolepsy.
      • Silber M.H
      • Rye D.B
      Solving the mystery of narcolepsy. The hypocretin story.
      It is reduced by structural lesions of the hypothalamus that cause hypersomnia,
      • Silber M.H
      • Rye D.B
      Solving the mystery of narcolepsy. The hypocretin story.
      and in paraneoplastic encephalitis with excessive daytime sleepiness and lethargy.
      • Overeem S
      • Dalmau J
      • Bataller L
      • et al.
      Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis.
      The neuropharmacology of this system explains why drugs with anticholinergic effects (e.g., opioids), or with antihistaminergic or gabaergic effects, are sedating, whereas monoaminergic (amphetamines) and serotonergic drugs are usually activating.
      • Pace-Schott E.F
      • Hobson J.A
      Basic mechanisms of sleep: new evidence on the neuroanatomy and neuromodulation of the NREM-REM cycle.
      The symptoms of metabolic encephalopathies could be explained by an effect on this neurotransmitter system.
      Modafinil is a relatively new drug that may influence this system. It has complex interactions with the dopamine and serotonin systems. It also acts at a hypothalamic level, most likely stimulating the tuberomammillary nucleus and hypocretin (orexin)-producing neurons, and it reduces GABA release in cortex and posterior hypothalamus. It, therefore, may activate wakefulness-promoting cerebral regions and inhibit sleep-promoting nuclei.
      • Scammell T.E
      • Estabrooke I.V
      • McCarthy M.T
      • et al.
      Hypothalamic arousal regions are activated during modafinil-induced wakefulness.
      • Ishizuka T
      • Sakamoto Y
      • Sakurai T
      • et al.
      Modafinil increases histamine release in the anterior hypothalamus of rats.
      It seems to be devoid of amphetamine-like activities and does not affect blood pressure or heart rate. It does not increase dopamine-like activities in the brain areas usually influenced by amphetamine. It could be seen as a selective pharmacological modulator of specific arousal systems.
      We recently treated two patients with modafinil, one with a structural brain lesion from ischemic damage and one with toxic-metabolic encephalopathy. These cases suggest that modafinil may be useful in palliative care.

      1. Case 1

      A 68-year-old man with left kidney adenocarcinoma was admitted to our hospital for left radical nephrectomy. His past medical history was significant for Type 1 diabetes and hypertension. On the second postoperative day, he had a stroke, with right hemiplegia, cortical blindness with retained ability to distinguish moving objects in the left visual field, and motor aphasia with retained ability to understand and perform verbal commands. Level of consciousness was significantly affected, as the patient could be kept awake only with vigorous verbal stimulation. Neurological findings were stable over time. Brain MRI showed a bilateral posterior cerebral infarct involving the left occipital lobe, the lower temporal gyri including the hippocampus, the posterior left thalamus, and the right occipital pole.
      Modafinil was administered at 100 mg twice daily. His level of consciousness improved. He was able to maintain wakefulness during the day and to participate in rehabilitation for 10 days, until discharged to a neurorehabilitation unit.

      2. Case 2

      A 65-year-old man with myelodysplasia and refractory anemia was followed for supportive therapy and repeated blood transfusion, and was a candidate for blood marrow transplant. He had high ferritin values and altered liver function (AST 93 U/L, ALT 93 U/L, gamma-GT U/L 52). Liver imaging (CT) was compatible with iron deposition. He developed progressive jaundice due to biliary stones (bilirubin 34 mg/dL with 25 mg/dL conjugated bilirubin, AST 177 U/L, ALT 246 U/L, gamma-GT 522 U/L) and pancytopenia. He was admitted for endoscopic biliary drainage, as surgery was prevented by the low platelet counts. After the procedure, bilirubin increased and sepsis with hypotensive shock and renal failure occurred. Antibiotics (ceftriaxone 2 g/day and amikacin 1,300 mg/day) were given, together with intensive care support of circulatory and renal functions. The patient developed bilateral hypo-acusia due to antibiotic toxicity. Bile and blood cultures demonstrated cholangitis and sepsis caused by pseudomonas, enterococcus fecalis and staphylococcus epidermidis, and antibiotic therapy was changed. After improving biliary drainage and providing antibiotic treatment, bilirubin decreased from 36 to 16 mg/dL. Leukocytes (630/μL) and platelets (3000/μL) remained low. Gastric hemorrhage occurred with laboratory evidence of disseminated intracascular coagulation. Slowly, he responded to therapy and began to improve.
      Progressive hypersomnia and daytime sleepiness developed during this course, as sepsis and fever resolved, renal function recovered, and bilirubin decreased to 2.6 mg/dL (AST 113 U/L, ALT 73 U/L, gamma-GT 57). At this time, ammonia levels were normal. The patient would fall asleep during conversations and was apathetic and hypoactive during most of the day. Neurological examination revealed bilateral deafness and bilateral Babinski signs. Brain MRI was normal, except for mild age-related cortical brain atrophy. EEG showed an alpha rhythm of relatively high amplitude in the right hemisphere, but within normal limits, and a spontaneous tendency to fall asleep during the recordings.
      Modafinil was given at 100 mg in the morning with immediate improvement of daytime wakefulness. This therapy was continued after the patient was discharged with full recovery of the acute septic state. His blood counts were still low and treated with the usual supportive therapies. Modafinil was continued for a few weeks and stopped after recovery of normal sleep-wakefulness cycle.

      3. Comment

      Modafinil has been approved for narcolepsy and recently was recommended for wider use by an advisory board to the U.S. Food and Drug Administration.
      • Ault A
      Narcolepsy drug could be approved for wider use.
      An interesting debate has arisen about the risks of using the drug nonspecifically for disorders associated with excessive daytime sleepiness, regardless of potential consequences as to the overall management of these disorders (i.e., treating the symptom without improving the cause).
      • Kingshott R.N
      • Vennelle M
      • Coleman E.L
      • et al.
      Randomized double blind placebo-controlled crossover trial of modafinil in the treatement of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome.
      • Pack A
      Should a pharmaceutical be approved for the broad indication of excessive sleepiness?.
      • Vastag B
      Poised to challenge need for sleep, “wakefulness enhancer” rouses concerns.
      In the meantime, research and anecdotal experience suggest that modafinil could be used to improve cognitive function, and to treat excessive sleepiness in Parkinson's disease, fatigue associated with multiple sclerosis, and other forms of secondary disturbances of wakefulness. It is presently also used off-label to treat sedation associated with opioid therapy for chronic pain.
      • Webster L
      • Andrews M
      • Stoddard G
      Modafinil treatment of opiod-induced sedation.
      Modafinil seems a very interesting drug for palliative care,
      • Pappagallo M
      Modafinil: a gift to portmanteau.
      a discipline which embodies the concept of treating the symptom on a rational basis when the cause cannot be addressed. It is our opinion that it would be important to design appropriate clinical trials in palliative care to address the use of modafinil for fatigue and opioid-induced sedation, which are well-known areas of clinical need in our specialty.

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