Psychopharmacology in supportive care of cancer: a review for the clinician. IV. Other psychotropic agents. Published online: 19 October 2000 q Springer-Verlag ...
Support Care Cancer (2001) 9 : 213–222 DOI 10.1007/s005200000191
T. Buclin C. Mazzocato A. Berney F. Stiefel
Published online: 19 October 2000 q Springer-Verlag 2000 T. Buclin Division de Pharmacologie Clinique, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland C. Mazzocato 7 F. Stiefel (Y) Division de Soins Palliatifs, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland E-mail: Frederic.Stiefel6chuv.hospvd.ch Phone: c41-21-31410 90 Fax: c41-21-3141098 A. Berney 7 F. Stiefel Service de Psychiatrie de Liaison, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland
SPECIAL ARTICLE
Psychopharmacology in supportive care of cancer: a review for the clinician IV. Other psychotropic agents
Abstract Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for secondline treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents
Introduction For the relief of psychological disturbances in the daily practice of palliative care, the clinician relies mainly on the three main classes of psychotropic agents reviewed in the previous articles in this series: the benzodiazepines [92], the neuroleptics [57] and the antidepressants [12]. Less frequently, other psychotropic drugs are of interest for the treatment of specific conditions in advanced cancer. Or, alternatively, agents not classified among the psychotropic drugs may be employed for their actions on the central nervous system. The aim of this article is to review a selection of substances from those two categories and consider their potential usefulness in supportive care. As a general comment, it is important to stress several points that must be taken into account when the prescription of such nonstandard or second-line psychotropic agents for advanced cancer patients is considered [14]:
requires that both their specificities and the particular characteristics of palliative care patients are taken into account. Keywords Psychotropic drugs 7 Palliative care 7 Supportive care
1. In most cases, the drugs will be used for an off-label indication. Outside the few standard classes, the data about specific psychotropic medications in supportive care are often scarce or absent. The therapeutic decisions will therefore rely more on clinical experience and reasoning than on published evidence. 2. The pharmacokinetics of drugs can be profoundly modified in patients with advanced cancer. The absorption may either decrease due to gastroparesis and achlorhydria, or increase due to impairment of the hepatic first-pass filter. Hypoproteinaemia, cachexia, dehydration or oedema can alter the drug distribution. And of course, liver and renal failure frequently jeopardise the elimination and favour the accumulation of the drug in the organism, thus increasing the risk of toxicity. 3. The pharmacodynamics of psychotropic agents can also be altered. In particular, their disrupting action on thought and consciousness may be enhanced by pre-existent hypoxia, metabolic imbalance, cerebro-
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meningeal dissemination of cancer cells or paraneoplastic secretion of chemical messengers. On the other hand, certain effects are characterised by some degree of tolerance and progressively decline during continuous exposure to a steady dosing regimen. 4. As several medications are often used concomitantly in palliative care patients, possible drug interactions may introduce further variability in the therapeutic response. Failure to recognise these interactions can lead to either overdosing or undertreatment [11]. 5. The practicability of selected treatments can be compromised, for example by difficulties in swallowing oral formulations, incompatibilities with enteral feeding formulations [37] or concerns about the repetitive recourse to the parenteral route. 6. The clinical condition of these patients is frequently unstable, characterised by spontaneous fluctuations, with a global trend towards progressive aggravation. This makes the evaluation of treatment outcomes particularly difficult, with a definite risk of confusion between medication failure, adverse effects and clinical events related to the progression of the underlying disease. For all these reasons, the clinician must pay particular attention to the validity of the indication and/or the rationale supporting the choice of the medication. The therapeutic objectives should be precisely defined in terms of clinical variables to be monitored throughout the treatment (e.g. by means of visual analogue scales, clinical scores) [14]. In parallel, safety parameters have to be followed up regularly (e.g. cognitive status, blood pressure and heart rate, intestinal transit, etc.). Keeping up a well-designed patient chart may be of critical importance. It is generally preferable to introduce the psychotropic drugs at the lowest possible doses, and to titrate the treatment progressively with respect to the clinical response and tolerance. Accordingly, there may be some advantage in introducing the drug quite early in the management of conditions requiring a psychotropic intervention, rather than waiting for full-blown symptoms. Adverse events have to be carefully recorded and analysed with respect to the entire treatment chart, to allow a formal evaluation of whether, and if so to what extent, they can be attributed to the medication [61]. Both the failure to recognise a side effect and the improper assignation of a clinical event to a drug can seriously compromise the patient’s welfare. These introductory comments are of special importance in the case of drugs for which the indication is based more on experience than on evidence and of drugs that are rarely prescribed and therefore remain unfamiliar to the palliative care specialist. This applies to the substances discussed in this paper.
Sedative, hypnotic and anxiolytic agents Sleep disorders are very frequent, occurring in up to 27% of the primary care population [50], and are more frequent in the elderly and those with advanced medical illness [2]. In order to restore sleep, hypnotics may be necessary. In fact, they are largely prescribed, and 30–40% of all psychotropic drugs given in a cancer setting are for sleep disturbance [45, 91]. Insomnia from psychiatric or somatic causes is not infrequent. Such comorbidity must be recognised prior to the introduction of hypnosedative drugs [83], as it can suggest the choice of more appropriate agents, such as tricyclic antidepressants [12], anxiolytic benzodiazepines [92] or neuroleptics [57]. Similarly, analgesia must be optimised before hypnotic medication is considered [9]. Drug-induced insomnia (e.g. with corticosteroids or bronchodilators) and the disruptive effects of alcohol, caffeine or nicotine on sleep should be identified. Excess daytime sedation with neuroleptics, antihistamines or sedative antidepressants may result in secondary insomnia. It must be recalled that reassurance, proper sleep hygiene and behavioural techniques such as relaxation are useful and should be evaluated before the introduction of a medication. As a general rule, hypnotics should be limited to short-term prescription, and intermittent use (two to four times weekly) at the lowest effective dose should be favoured, because of the risks of tolerance, dosage escalation and physical dependence [49]. While these concerns are certainly of less importance in the palliative care setting, the exceptional sensitivity of these patients to the side effects of hypnotic drugs must be emphasised. Moreover, the abrupt discontinuation of such medication, for example on hospital admission, may produce nonspecific withdrawal symptoms that are not easy to recognise. However, this is not a sufficient reason for perpetuating an established prescription when it is deemed useless [18]. Benzodiazepines continue to be the most commonly prescribed hypnotics and anxiolytics [92]. Such agents can be poorly tolerated, e.g. because of residual daytime sedation [103], anterograde amnesia, delirium, paradoxical agitation [40] or drug interactions [104]. Thus, in some cases, alternative choices deserve consideration for sleep induction or anxiety relief. We therefore discuss some second-line therapeutic agents that can be used in these indications. Benzodiazepine analogues Zolpidem and zopiclone, although not belonging to the chemical class of benzodiazepines, share many pharmacological features with this group of drugs. Their clinical effect profile is probably explained both by phar-
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macokinetic considerations and by the relative low dosages of the preparations commercially available; their relative specificity for a subset of GABA receptors also plays some part [25]. The rapid absorption and short half-life of zolpidem makes it a suitable agent for sleep induction, since there is no morning hangover effect [27, 51], while the slower kinetics of zopiclone suggest its use for night awakening [67]. These agents can be prescribed as an alternative to classic benzodiazepines, with similar indications and safety warnings. In particular, they can precipitate confusion, paradoxical reactions and falls, and they may also induce dependence with long-term use [70, 94].
[64]. It is also effective in the treatment of excitation states arising from other causes, and several geriatricians use it as a first-line hypnosedative in patients with nocturnal agitation associated with cognitive impairment, at the dose of 300 mg p.o. [7, 24, 39, 69]. It seems to induce less confusion and fewer paradoxical effects than the benzodiazepines. As it may both depress the ventilation and increase the bronchial secretions, it is contraindicated in patients with respiratory impairment. Prolonged use tends to induce dependence. Chlormethiazole may be considered for the treatment of insomnia and nocturnal agitation in palliative care patients, once reversible causes of such manifestations have been recognised and corrected (e.g. pain, urinary retention, dehydration, hypoxia).
Barbiturates and carbamates Drugs in this group have been withdrawn from the market in several countries, because of their high abuse potential and narrow therapeutic margin. The prescription of pentobarbital, meprobamate or methaqualone does not generally make sense in palliative care. It may be considered at most for patients who have been severely addicted to hypnosedative agents over a prolonged period and who present with intractable anxiety and insomnia complicating terminal illness. Caution must be exercised because of the significant risk of coma with respiratory arrest in the case of accumulation or overdosage. Moreover, these agents are inducers of hepatic enzymes and may decrease the effectiveness of various drugs, including analgesics. Chloral hydrate Chloral hydrate, one of the oldest hypnotic drugs, is well tolerated as a sleep inducer. It is considered less effective than the compounds cited above, but may also induce less confusion and fewer paradoxical reactions [38]. The recommended initial dosage is 250 mg at bedtime, followed by progressive titration up to 500 or even 1,000 mg. The oral solution allows appropriate dose adjustment, but its unpleasant taste makes it essential to dilute it with fruit juice. Capsules or tablets are available as an alternative. Problems are its poor digestive tolerability and relatively narrow therapeutic margin, with cardiac toxicity possibly occurring either at high doses or in the presence of cardiopathy [49]. As for other hypnotics, regular use of chloral hydrate induces tolerance and physical dependence. Chlormethiazole This vitamin B1 derivative has been introduced primarily for the treatment of alcohol withdrawal syndrome
Histamine antagonists This class comprises various compounds, such as promethazine, diphenhydramine and hydroxyzine. Their antagonistic action on histamine H1 receptors in the brain results in sedation, stimulates appetite and decreases nausea. A slight antidopaminergic activity may partly account for their tranquillising effects. Moreover, the antihistamines are antipruritic and have some analgesic effect on their own [79]. They tend to reduce daytime alertness, because of their prolonged half-life [8] and can potentiate the sedating effects of narcotics. Most compounds in this class also have anticholinergic properties, which can elicit mouth and eye dryness, constipation, urine retention, and cognitive impairment. High doses can precipitate confusion, delirium, convulsions and cardiac arrhythmia [20]. Occasionally, prolonged use may cause cholestatic hepatitis. In total, these drugs are rarely useful in the palliative setting, and only at small doses. Melatonin Melatonin, an endogenous neuro-hormonal agent, participates in the regulation of the physiological circadian cycle. While it is commercially available in the USA as a “nutraceutical”, it is not registered in most European countries at present. Besides its effectiveness in jetlag-related insomnia [73, 96], some beneficial sleep-regulating activity has been alleged [106, 107]. It might also have an analgesic adjuvant effect and counteract the mechanisms of cancer-related cachexia [53]. The recommended doses range from 3 to 10 mg 2 hours before bedtime. Compared with all the previously mentioned compounds, melatonin has a relatively weak sleep-inducing activity. However, its excellent tolerability and the fact that it is seen as complementary medicine can make it acceptable for patients who are reluctant to take potent psychotropic drugs.
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Buspirone The pharmacological effects of buspirone are thought to derive from its partial agonistic action on the 5HT1A serotonin receptor. It also has a slight antidopaminergic activity. Compared with the benzodiazepines, buspirone is characterised by a favourable side-effect profile and a low abuse potential. It does not cause sedative and respiratory depressant effects, cognitive and psychomotor impairment, or significant withdrawal symptoms. It is mainly useful in psychiatric conditions, particularly in patients with persistent anxiety and anxiety related to adjustment disorders [5]. As the anxiolytic effect of buspirone gradually evolves over 1– 3 weeks, its use is questionable in terminal conditions. The initial dose is 5 mg two to three times daily, which may be progressively increased up to 30 mg daily. Such side effects as dizziness, headache, and nausea are usually transient and subside as treatment continues [89]. Buspirone has been shown to stimulate respiration experimentally [36, 58] and in patients with lung disease [23]. A controlled, double-blind study reports improvement in exercise tolerance and dyspnoea in 16 patients with COPD during buspirone treatment [6]. However, these data are not confirmed by another study [87].
Anaesthetics Occasionally, intense pain, severe anxiety or delirium resistant to conventional medications require that more potent therapeutic alternatives are considered for the supportive care of terminally ill patients. The use of general anaesthetic agents raises ethical concerns, however: the risk that this might actively precipitate death is obvious, but in addition to this, disruptive effects on thought and consciousness may deprive the patient and his or her significant others from important end-of-life exchanges [98]. In any case, these agents should not be introduced before full optimisation of the treatment has been attempted. While such drugs may be the only appropriate response to unbearable symptoms, one must be careful that they are not prescribed to treat the caregivers’ suffering rather than the patients’ own. Teamwork and supervision can be of crucial help. Ketamine This agent induces a state of “dissociative anaesthesia” with partial preservation of consciousness, a marked degree of indifference towards both the somatic symptoms and the environment, and an oneiroid state of variable intensity. Compared with other anaesthetics, it
causes minimal impairment of spontaneous ventilation, muscular tone and cardiovascular state. It is usually administered via the intramuscular route, by slow intravenous injections or even intrathecally on an asneeded basis [52], but oral administration of the parenteral solution is also possible [30]. The duration of effect ranges from half an hour to several hours. Beneficial effects of ketamine have been reported in intractable pain states complicating advanced cancer [22, 33, 42]. Ketamine may also have antidepressant properties [10]. The most common side effects are cardiac acceleration, hypertension and the appearance of dysphoric mood with strange feelings and possibly nightmares. Propofol This agent is administered intravenously and induces sedation, sleepiness or profound sleep, depending on the circulating concentration levels. It is widely used to induce and maintain general anaesthesia, and for patient sedation in intensive care units. It may be used as a last resort in hospital palliative care, under close monitoring [59, 65]. The infusion rate must be adjusted to the clinical response, considering that accumulation or decay occurs progressively over 12–36 hours after rate increase or decrease, respectively. Infusion rates reported to provide adequate sedation vary between 5 and 50 mg kg –1 min –1. Oversedation can lead to cardiovascular collapse and respiratory arrest. Propofol occasionally induces anaphylactic reactions or acute respiratory distress. The infusion solution should not be prepared in advance, because it represents an ideal culture medium for bacteria or fungi in case of contamination.
Stimulants There are two main types of indications for drugs capable of stimulating the central nervous system in supportive care: first, they are used to reverse the sedation caused by opioid analgesics, and secondly, they can alleviate a whole range of symptoms frequently encountered in advanced cancer patients, extending from intense fatigue to major depression. Unlike the antidepressants, they develop their effects without delay, which may be particularly appropriate in terminal illness [54]. Through their actions on alertness and attention, they can improve various manifestations of cancer-related brain damage [62], AIDS-related encephalopathy [3, 13], or hypoactive, hypoalert delirium [90]. Furthermore, controlled studies have shown that psychostimulants potentiate the analgesic effects of narcotics [16, 17, 34]. However, the prescriber must keep in mind that stimulant drugs readily induce
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tolerance and physical dependence, and that impressive rebound symptoms may occur on abrupt drug withdrawal even after only a few days of treatment. Selected patients can derive a real advantage from such treatment and should not be denied a trial whenever therapeutic efficacy seems possible. The place of psychostimulants in supportive care has recently been reviewed in detail in this journal [44].
is generally 3–8 hours. The safety profile of methylphenidate in elderly patients is satisfactory, but caution should be exercised in the case of cardiovascular instability, abnormal movements, seizure disorders, preexisting confusion or marked anxiety. The drug may induce insomnia, anorexia and, rarely, hyperactive delirium or hallucinations. It should not be withdrawn abruptly.
Amphetamines
Caffeine
Dextroamphetamine is difficult to obtain in several countries, because it is classified as a narcotic. The drug readily increases alertness and lightens mood, effects connected with its general activating effect on noradrenergic and dopaminergic neural transmission. It has definite appetite- and sleep-suppressant activities and raises the blood pressure. It can precipitate cardiovascular and also psychiatric events, such as nervousness, anxiety and agitation, and it is highly addictive. It has been progressively abandoned in favour of methylphenidate. The same is also true for cocaine.
Caffeine is a mild stimulant regularly used by a significant percentage of the general population. It probably acts as an adenosine receptor antagonist rather than through phosphodiesterase inhibition, as previously thought, and indirectly increases the catecholaminergic neurotransmission. It has tangible effects on alertness and subtly enhances mood. Its analgesic efficacy in various painful conditions is definite but modest [85, 105], and might be most pronounced in the case of headaches [84]. The abrupt withdrawal of caffeine after prolonged daily consumption, even of low doses, produces substantial symptoms in a high percentage of people, including headaches, oversedation and transient depression [31, 47, 86]. This is a frequent, underrecognised, cause of symptoms associated with hospital admission [100]. Although caffeine has not been evaluated formally in the supportive care of patients with advanced cancer, it may certainly help some patients in whom mild stimulation is desirable. This can be achieved by means of caffeinated beverages rather than caffeine tablets. A 100-mg dose corresponds roughly to one cup of coffee. The daily dosage varies from 100 to 400 mg, preferably given in the morning and at noon to avoid sleep disturbances.
Methylphenidate The pharmacodynamic properties of this stimulant are roughly similar to those of the amphetamines. However, they are reported to be less pronounced, owing both to their different specificity for various neurotransmitter systems in the brain and to the relatively lower labelled dosage. It is widely used in the United States for the treatment of childhood attentiondeficit hyperactivity disorder. It has been applied with variable success in the treatment of depressive states, in particular in elderly or demented patients [29, 48]. In a double-blind, crossover study, methylphenidate significantly decreased pain and sedation in cancer patients receiving high-dose narcotics. Toxicity was not significantly different from that of placebo, and 70% of the patients assessed methylphenidate blindly as more effective [17]. It has also been proposed for the supportive treatment of HIV patients with depression [32] or cognitive impairment [13]. While favourable responses have regularly been reported in depressed or oversedated terminally ill patients [17, 35, 56, 68, 78, 99, 101, 102], the clinical significance of this effect has been questioned [55]. The initial dosage is 2.5 mg in the morning; it must be progressively titrated, with due consideration to the clinical response and tolerance, up to 10 or 20 mg b.i.d., to be administered in the morning and at noon to avoid sleep suppression. The duration of the stimulant effect
Analgesic adjuvants Many psychotropic medications can be used as co-analgesics in advanced cancer patients presenting with painful symptoms. In these circumstances, it is recommended that the drug be chosen with due consideration for its psychopharmacological profile: for example, antidepressants are preferred in the presence of depressive symptoms, and neuroleptics in the case of anxiety with irrational concerns. The use of neuroleptics, benzodiazepines and antidepressants as co-analgesics has already been reviewed in the first three papers in this series [12, 57, 92]. Other medications used as adjuvants for analgesia have psychopharmacological characteristics, which can be of benefit for selected patients. Conversely, these characteristics can represent relative contraindications to their use.
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Anticonvulsants Most of the anticonvulsants have sedative properties, which are more pronounced on introduction and progressively subside over the subsequent days or weeks [81]. This is particularly true for clonazepam and clobazam, which belong to the same chemical class as benzodiazepines, and for phenobarbital and carbamazepine. This effect can make it possible to decrease the dose of other sedatives. It can also increase the disorientation and confusion in patients with pre-existing cognitive impairment. Valproate is an exception, as it is almost completely devoid of sedative effects. Gabapentin also appears to be well tolerated: an open study reported an improvement in neuropathic cancer pain without an increase in sedation [19]. The anticonvulsants are mainly used in patients suffering from cancer pain associated with tumoural nerve involvement, which is the classic indication for anticonvulsant co-analgesia. Nevertheless, most of the evidence available for their analgesic effects in cancer patients results from anecdotal reports or open trials. The anticonvulsant benzodiazepines are highly effective in anxiety disorders [92, 108]. Several anticonvulsants are also mood stabilisers and have been shown to be effective both as prophylactic and as add-on treatment for depressive disorders [75, 95]. Given the lack of knowledge about their effectiveness in depression associated with advanced cancer, their use for mood restoration should be based on the advice of a mental health specialist. Finally, it is recalled that many anticonvulsants induce liver enzymes and can therefore reduce the effectiveness of other drugs eliminated by liver metabolism, such as methadone, tramadol, midazolam, sertraline or haloperidol [63, 77, 88, 97]. Gabapentin seems to be devoid of major drug interactions as it does not induce or inhibit hepatic enzyme activity. It might therefore represent an attractive adjuvant drug in advanced cancer patients who are already receiving multiple medications [19]; the daily dosage must be adapted in the presence of renal failure. Dextromethorphan Dextromethorphan is increasingly used as an analgesic adjuvant [21, 82], despite controversies about its true effectiveness in advanced cancer [60]. This drug has psychotropic effects and abuse potential, while it produces thought disruption and an oneiroid state at high doses [66]. It can precipitate psychosis in predisposed patients [74, 76]. It is a specific substrate of the CYP2D6 isoenzyme of cytochrome P-450, which is deficient in about 7% of the caucasian population. Such slow metabolisers are thus at risk of developing toxicity when this drug is used at the conventional dosage [93].
It is still not clear whether the psychotropic effects of dextromethorphan could be used profitably in supportive care of cancer.
Steroid hormones Corticosteroids are widely used as co-analgesics in advanced cancer patients. They occasionally produce overt psychotic decompensation mimicking a manic episode [71]. More frequently, they only induce slight or moderate mood changes, which often go unrecognised as a genuine psychotropic effect but which probably participate in their overall therapeutic efficacy. The mechanisms of this effect are still poorly understood, but may involve specific receptors on neuronal membranes [80]. A double-blind, crossover study revealed an initial improvement in pain, appetite, and activity with methylprednisone. Patients blindly assessed methylprednisone as more effective than placebo in 75% of cases [15]. However, after 3 weeks of treatment, pain intensity was the only one of the variables checked that was significantly different from the baseline assessment. Megestrol acetate, previously used as adjunctive hormone therapy for breast, prostate, endometrial and renal carcinoma, is presently employed as an appetite stimulant and anabolic agent in patients with cancer or AIDS-related cachexia. This compound might share sedative, anxiolytic and antidepressant properties with other progestational agents, again through interaction with specific receptors in the brain [80]. Although this psychotropic effect is hypothetical, it might contribute to improving the quality of life of palliative care patients. Progress is expected in this area, and steroid research may provide new therapeutic opportunities for palliative care.
Anticholinergic and antiemetic agents Visceral cramps associated with abdominal malignancies can be efficiently alleviated by anticholinergic drugs such as atropine and scopolamine, also active as antiemetics. Such drugs also have psychotropic side effects, often undesirable in the setting of palliative care. They produce variable degree of cognitive and memory impairment. While this effect often remains clinically undetectable, it can precipitate confusion and delirium, particularly in elderly subjects and in patients with pre-existing brain dysfunction. Such undesirable manifestations are less likely to occur with cationic agents such as butylscopolamine, propantheline or glycopyrrhonium, which have poor passage through the blood–brain barrier.
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Among the other antiemetic agents, metoclopramide deserves a mention for its mild neuroleptic activity, which can be beneficial for certain patients, while it may also induce distressing extrapyramidal side effects [72]. Droperidol and haloperidol are other neuroleptics used against nausea and vomiting. Domperidone and alizapride, in contrast, are practically devoid of neuroleptic activity. Cannabis derivatives The therapeutic roles of the cannabinoids in palliative care are still subject to vigorous controversies [28]. An increasing number of authors agree on the fact that either natural extracts (hashish, hemp oil) or active derivatives (dronabinol, nabilone) might have adjunctive analgesic, antiemetic, appetite-stimulant and antispasmodic effects in a subset of patients with terminal cancer. In parallel, the pharmacological target of this class of agents has recently been identified as the anandamide receptor, a neurotransmitter system employing arachidonic acid derivatives [1, 26]. This system is thought to exert modulating influences on pain perception independently of the endogenous opioids [43]. Evaluation of the therapeutic potential of cannabinoids in various medical indications is coming progressively closer to reaching a consensus [41, 46]. This appraisal, however, is complicated by unavoidable psychological and sociological messages delivered to patients along with hemp derivatives, and by the risk that subjective efficacy assessments are biased by drug-induced cognitive distortions. It is still too early to make precise recommendations on the use of cannabinoids in supportive care. However, this treatment certainly deserves consideration in selected individual cases, e.g. patients with refractory pain associated with inner tension, muscle spasms, nausea and anorexia. The patient’s willingness or otherwise to receive a cannabis derivative must also be taken into account. Preference should be given to the purified active ingredient dronabinol, which is commercially available in several countries, including the USA. Treatment is usually started at 2.5 mg three times daily, and the dosage is then titrated with regard to clinical effectiveness and tolerance. The most frequent side effects are drowsiness, dysphoria, tachycardia and malaise. Such events can necessitate discontinuation of treatment in a significant proportion of patients.
Conclusions The management of symptoms and disturbances occurring in advanced cancer patients is a difficult task. Such manifestations are frequent and multifactorial, with
components related to biological factors, such as the extension of the malignant disease, metastatic brain involvement, metabolic disturbances, paraneoplastic hormone and cytokine secretions, hypoxia and nutrient deficiencies, but also to the patient’s personality, life history, success in coping with the disease, the family and social environment, the patient’s medication and drug habits. Accordingly, it is appropriate that therapeutic interventions are also multimodal. Although diagnostic investigations must remain restricted to the palliative care setting, the possible biological components of psychological disturbances deserve consideration, as they may be amenable to specific correction. On the other hand, the importance of qualified and empathic psychological care has to be emphasised. In this context, prescription of drug(s) represents only one element of the treatment. It is, however, of importance that the right drug is administered for the right indication, at the correct dose and frequency, and with adequate monitoring of predefined therapeutic outcome variables and safety indicators [14]. As already mentioned, the assessment of treatment effectiveness is further complicated by confounding factors, such as the evolution of underlying disease, fluctuations in the clinical state, intercurrent complications, drug interactions, and non-drug effects, including suggestion (placebo effects) and relational factors. As indicated by this series of review papers about the psychotropic medications in supportive care, a fairly wide palette of drugs is available to help patients. However, the prescriber must keep in mind that all the pharmaceutical treatments presented here are only symptomatic, without any pretensions to treating the underlying causes. So it is perfectly justified, and even advisable, for clinicians to limit their first choice of psychotropic prescription to a few, carefully selected compounds from the reference classes [12, 57, 90]. Only in a minority of cases will recourse to alternatives be appropriate. The relative lack of data about many specific psychotropic medications in palliative care has already been stressed. Probably much remains to be learned about the optimal drug support that can be provided to advanced cancer patients. Informative case reports deserve publication. Whenever possible, a formal appraisal of the effectiveness of treatment must be encouraged. Ideally, two or more therapeutic alternatives can be compared in well-designed, small clinical trials involving randomisation and intention-to-treat analysis. In selected conditions, an “n-of-one trial” set up for an individual patient may also yield valuable information [4, 42]. It is our hope that this paper will stimulate clinicians both to use psychotropic medications rationally for the greatest possible benefit of palliative care patients and to expand knowledge in this area.
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