11.2 Pruritus and sweating in palliative medicine

Itching (pruritus) and sweating (perspiration, diaphoresis) are physiological functions of the skin that normally serve human existence well. Itching is the sensory input arising from the skin and mucous membranes that alerts man to potentially harmful insults from physical, chemical, and biological sources. The reflex of scratching is closely linked to the perception of itch, and in most situations functions effectively as an aversive motor response to relieve the sensation and protect the skin. Similarly, sweating is a well-developed and finely coordinated sudomotor response designed to regulate body temperature and prevent hyperthermia.

However, both pruritus and sweating have the potential to function aberrantly and develop into pathological conditions that create significant suffering and morbidity. Since these skin responses encompass both normal and abnormal functions, effective treatments to alleviate or eliminate the pathological component are challenging. In this chapter we provide a practical overview of the normal function and pathophysiology of pruritus and sweating, and offer a variety of therapeutic options and general comforting measures for patients experiencing these maladies.

Itch and pruritus are terms used to describe both physiological and pathological sensory perception. Itch is a distinctive and common cutaneous sensation that arises from the superficial layers of the skin and mucous membranes. It is often fleeting, and the sensation may pass relatively unnoticed since the reflex action of scratching is largely involuntary and typically relieves the temporary discomfort.

Itch (itching, itchy, or itchiness) and pruritus (from the Latin prurire, to itch) are generally considered to have equivalent meanings. Itch and related descriptions such as ‘terrible itching’ are terms commonly used by the patient to convey this distinctive symptom. However, subtle differences in the terminology of itch and pruritus have evolved in the medical literature. In this respect, the terms itch and pruritus have been used to characterize the spectrum of unique cutaneous sensations ranging from the physiological response to severe pathological symptoms (Winkelmann, 1961; Winkelmann and Muller, 1964; Gilchrest, 1982; Denman, 1986; Bernhard, 1994). Physiological itch is the short-lived cutaneous response to the usual events of living, while pruritus is more closely associated with pathological itch (Winkelmann and Muller, 1964; Bernhard, 1994). Use of the term pruritus represents the symptomatic level or quality of itch that is defined as an intense cutaneous discomfort occurring with pathological change in the skin or body and eliciting vigorous scratching.

The definition of pruritus or itch is subjective and not entirely precise. Although the general sensation is well known and implicitly understood, many patients with more severe symptoms assimilate itch with various other discomforting or unpleasant sensation. The term itch frequently encompasses a range of descriptive or qualifying terms such as tickle, prickle, pins and needles, burning, stinging, chafed, raw, aching, and even ‘painful’ sensations (Bernhard, 1994).

To avoid confusion and to focus on the palliative medicine perspective, the terms itch and pruritus are used interchangeably to describe this pathological symptom. Patients experiencing pruritus may develop this symptom only mildly and transiently, or itching may be so severe and unrelenting that it preoccupies and completely disrupts their daily existence. It must be recognized that itch or pruritus is variable in its perceived quality and intensity. As with pain, the perception and tolerance of pruritus and the response to this sensation depends significantly on the individual’s physical and emotional states, the functional level of activity, adaptive coping mechanisms, and the overall outlook. Attempts to develop questionnaires that assess severity of pruritus have been developed based on modified pain questionnaires (Yosipovitch et al., 2001). These quantitative measuring tools will be useful to better standardize symptoms and treatment responses.

Pruritus is a discrete sensation and a primary sensory modality arising from the activation and integration of cutaneous sensory neural receptors, afferent pathways, and central nervous system processing centres (Paus et al., 2006) (Fig. 11.2.1). In the past, itch was considered to be a low-threshold form or submodality of pain based on various clinical and experimental observations. Both pain and itch are induced by noxious stimuli and therefore are designated ‘nociceptive’.

A prevailing theory was that itch and pain were related sensations that differed only in the strength of the stimulus, with itch being a response to a weak stimulus and pain being elicited by a stronger stimulus. Further investigation of pain and pruritus not only revealed similarities but also clearly demonstrated the distinctive differences between these two sensations. Recent research has conclusively demonstrated that itch and pain are represented by distinct nerve fibres. Itch neurons are specific type C fibres in skin, each having a wide innervation territory, thin axon, and very low conduction velocity (Schmelz et al. 1997). The central neural pathway for itch has also been recently localized to spinothalamic lamina I neurons that are selectively sensitive to histamine (Andrew and Craig, 2001).

Many definitions of pruritus specifically include the reflex action of scratching. Scratching illustrates the distinctive sensation of pruritus, and the scratching reflex is routinely elicited and intimately coupled to itch. Scratching is regarded as a protective reflex, much as withdrawal (flexion) and guarding are comparable reflexes in response to painful stimuli.

Pruritus is induced in skin by various stimuli. Both exogenous and endogenous factors have the capacity to elicit itch (Hägermark, 1992; Wallengren, 1993). Most experimental and spontaneous triggering factors are mediated via the exogenous or external route. Cutaneous sensory nerves which convey the pruritic signal become activated through the application of either physical or chemical stimuli to the skin (Fig. 11.2.2). Many physical stimuli induce pruritus, including pressure, thermal stimulation, low-intensity electrical stimulation, formation of suction blisters, and epicutaneous application of caustic substances.

Chemical stimuli include histamine, proteases, prostaglandins, and neuropeptides (Pauset al., 2006). Delivery of histamine to the upper layers of skin by injection or iontophoresis has been a quantitative and reproducible method of examining pruritus experimentally. Histamine is also secreted in skin by mast cells. It acts directly on free nerve endings in skin.

Proteases such as trypsin, chymotrypsin, papain, and kallikrein have the ability to induce pruritus when injected into skin. For example, the spicules of the plant cowage (Mucuna pruriens) contain an endopeptidase. These fine spicules are an active ingredient of itching powder and induce an itching sensation when they penetrate into the epidermal layers or dermoepidermal junction of skin. Other natural proteases produced in cells and tissues of the body or by microorganisms such as bacterial or fungal microflora of the skin also have the potential to induce pruritus.

The nerve fibres that conduct signals representing itch are located predominantly at the epidermal–dermal junction and have free endings extending into the epidermis (Wallengren, 1993). The afferent sensory neurons that mediate these separate stimuli are distinct subsets of pruritogenic fibres (Dhand and Aminoff, 2014). Many of these nerve fibres contain neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide (Fig. 11.2.2). Other neuropeptides contained in nerves deeper in the dermis and located around blood vessels include vasoactive intestinal peptide and neuropeptide Y. Substance P, which is the best-characterized pruritogenic neuropeptide, is a sensory transmitter of nociception. It is localized to sensory nerve endings in the skin and is abundant in the prevertebral ganglia, the dorsal roots of the spinal cord, and the brain. Administration of substance P intrathecally causes intense scratching that can be blocked by an antagonist. Nerve fibres containing substance P appear to transmit direct synaptic sensory impulses for the itch sensation.

Capsaicin, an alkaloid derived from the common pepper plant, is a well-known stimulant of erythema and pain when applied to mucous membrane or skin. It depletes substance P from the sensory nerves and excites the type C polymodal nerve fibres conveying pain. However, after initial stimulation, capsaicin blocks C fibre conduction and mediates neuronal toxicity which eventually decreases fibre density. These activities of capsaicin have stimulated the use of this agent for the treatment of pruritus (Bernstein, 1992).

Neuromediators directly influence vascular permeability and erythema (Fig. 11.2.2). They also activate release of other mediators such as interleukins, prostaglandins, bradykinin, serotonin, and histamine from infiltrating leucocytes and tissue-localized mast cells. Together, these neural and cellular mediators induce the sensation of itch, augment local activation of inflammatory responses that often accompany itch, and create areas of hyper-responsiveness around the primary stimulus zone for itch. For example, the phenomenon of ‘itchy skin’ (alloknesis) may be due to regional hyper-responsiveness as well as a lowering of the threshold to itch stimuli at the level of the spinal cord. Additionally, neuromediator release is probably augmented through antidromic nerve stimulation.

Human skin is supplied principally by nerve fibre networks composed of A and D myelinated fibres and thin type C unmyelinated fibres. Afferent type C fibres include C mechanoreceptors, cold thermoreceptors, C polymodal, and C itch nociceptors. Itch is primarily conveyed by the C itch fibres which represent approximately 15–20% of unmyelinated nerve fibres in skin. The remaining polymodal C fibres constitute about 80% of all afferent C fibres (Fig. 11.2.1). The exact location and unique identity of the itch receptor is unknown, but it is likely resides in free nerve endings.

Itch, therefore, is separate from the slow, aching, dull, or burning pain that is conducted by type C polymodal fibres (Winkelmann, 1988; Handwerker et al., 1991). Myelinated A delta nociceptors conveying sharp pain also have been identified. Physiological and pharmacological studies have shown that separate independent sensory channels conduct itch and pain stimuli. The latency between stimulation and onset of the sensation of pain coincides with the relatively low rates of conduction (2 m/s) by the neurons that serve these sensory functions. Itch fibres have very slow velocities of 0.5–0.7 m/s (Schmelz et al., 1997; Andrew and Craig, 2001). Some investigators have suggested separating ‘itch’ into the ‘pricking’ sensation carried by myelinated fibres and the ‘burning’ sensation conveyed by unmyelinated fibres. This classification of sensations correlates with the two different systems of sensation described by Head (Head, 1905) in 1905 as the epicritic or specific well-defined sensation that mediates spontaneous itch and the protopathic or diffuse poorly localized sensation that conveys the perception of itchy skin. On the basis of current scientific knowledge pain and itch are largely separable cutaneous sensations. However, there is evidence of secondary neuron interactions with ‘itch-specific’ fibres being suppressed by coactivation of pain nociceptors using agents such as capsaicin.

In addition to the external or exogenous pathway for initiation of the itch sensation, there is considerable clinical evidence for the endogenous activation of pruritus (Winkelmann, 1961; Winkelmann and Muller, 1964; Gilchrest, 1982; Denman, 1986; Bernhard, 1994) (Fig. 11.2.2). The endogenous route for stimulation of pruritus represents a major and clinically relevant pathway; however, it is poorly understood. The potential sites of stimulation (the peripheral nervous system, the spinal cord, and/or the central nervous system), the inciting agents and mediators, and the relative overlap of exogenous versus endogenous activation pathways remain to be clearly delineated and applied effectively in the clinical setting. The systemic or endogenous stimuli for itch have been only partially characterized, and the biochemical causes for pruritus associated with a spectrum of systemic illnesses, including metabolic disease, organ failure, and various malignancies, continue to be ill-defined and vexing problems. One recently identified and novel endogenous mediator is lysophosphatidic acid which is markedly elevated in cholestatic pruritus and is an intense pruritogen when injected into the skin (Oude Elferink et al., 2011).

Several substances have been shown to mediate different or opposing effects on itch when tested experimentally. Their activities depend on the route of administration and their specific responses at the peripheral, spinal cord, and/or central nervous system levels. These observations support the concept of itch as a neural message that is interpreted in the context of signal reception, transmission, and modulation at each level of the nervous system.

Opioids are one example of substances that exert separate and potentially disparate responses in modulating the transmission and perception of itch and pain at different levels of the nervous system (Lowitt and Bernhard, 1992; Bernhard, 1994). Uncovering the existence of central opioid receptors led to the discovery of encephalins, endogenous pentapeptides that bind to these receptors. Opioids are powerful analgesics that mimic the effects of encephalins. However, opioids mediate both excitatory and modulatory effects on pruritus at several levels. At the spinal level, encephalins released from short spinal interneurons and opioids stimulate an inhibitory presynaptic signal transmitted to primary afferents that modulates secondary transmission of itch. However, within some regions of the central nervous system, opioids directly trigger itch. Clinically, intrathecal or epidural morphine has been known to induce localized or generalized itching. At the peripheral level within skin, opioids stimulate mast cell degranulation and release of histamine which produces itch. Furthermore, based on the recent identification and characterization of itch-specific primary nerve fibres, opioids may induce itching by blocking the painful stimuli that suppress activity of central itch neurons.

Central activation of itch by opioids appears to play a dominant role in some diseases, since opioid antagonists have been shown to exert significant antipruritic effects (Lowitt and Bernhard, 1992; Bergasa et al., 1995). The parenterally administered opioid antagonist naloxone inhibits induction of itch following histamine injection of skin. Pruritus of cholestatic liver disease (primary or secondary biliary cirrhosis) can be dramatically reduced with naloxone or the oral antagonist nalmephene (Khandelwal and Malet, 1994; Paus et al., 2006).

Serotonergic compounds are another group of agents that modulate effects on pruritus primarily at the peripheral level, although receptors for serotonin are present in the peripheral and central nervous systems. Cutaneous injection but not intravenous infusion of a serotonergic agonist increases the scratching reflex in animals. Peripheral serotonin receptors in humans are presumed to play a role in the mediation of pruritus. Temperature-dependent pruritus experienced by patients with polycythaemia vera may be stimulated by serotonin. Serotonin reuptake inhibitors, specifically paroxetine, have recently been reported to be useful for treatment of polycythemia vera-related pruritus (Diehn and Tefferi, 2001). Of potential clinical significance, generalized pruritus of hepatic cholestatic disease and chronic renal insufficiency have been relieved dramatically with intravenous administration of the type 3 serotonin (5-HT₃) receptor antagonist ondansetron (Schworer and Ramadori, 1993; Radereret al., 1994). However, other recent placebo-controlled studies have refuted this finding in uraemic pruritus (Ashmore et al., 2000). Nonetheless, opioid and serotonin receptor antagonists have revealed the complex mechanisms involved in transmitting signals for pruritus at the peripheral and central nervous system levels.

The similarity of the symptoms of exogenous and endogenous forms of pruritus has prompted empirical use of similar treatment measures for both types of conditions. Frequently, however, effective therapy for pruritus caused by one condition is not particularly beneficial for pruritus of another cause. Also, treatments that ameliorate or relieve pruritus induced by exogenous agents have limited or minimal effects on alleviating pruritus of endogenous cause. This is probably related to the site and mode of activity of these treatments and their limitations in targeting the receptors, mediators, or central neural pathways that control expression of endogenous versus exogenous pruritus.

The nuclei of the afferent C itch and polymodal nerves reside in the dorsal root ganglia and axon extensions that synapse in the dorsal horn of the substantia gelatinosa (Fig. 11.2.1). Secondary neurons cross the spinal cord to the contralateral spinothalamic tract of the venterolateral quadrant before ascending to the thalamus. Lamina I of the spinothalamic tract contains type C itch fibres (Andrew and Craig, 2001). There is also evidence in animals that pathways in addition to the anterolateral system can transmit pruritogenic stimuli. Both the ventral posterior inferior nucleus and the ventral periphery of the ventral posterior lateral nucleus of the thalamus contain itch fibres projecting from lamina I (Andrew and Craig, 2001). The synaptic neurons within the thalamus project to the somatosensory cortex of the postcentral gyrus. Scratching is the spinal reflex in response to itching but also has input from higher neural centres.

Perception of itch has the potential to be modulated at the level of the spinal cord and, probably at other levels, by additional neural input as described for pain by Melzack and Wall (1965). The description of ‘a gate control system that modulates sensory input from the skin before it evokes pain perception’ can also be applied to the perception of itch.

A fibre impulse conduction is self-regulated by a negative feedback pathway that tends to dampen continued firing. It also interrupts summation of sensations of itch and pain conveyed by the C itch and polymodal fibres. The ‘gate’ has the ability to control neural transmission. Gate closure is envisaged to produce inhibition at the spinal cord level such that stimulation of A fibres by scratching would induce or enhance inhibition of conduction. Although the gate-control theory has been intensively evaluated and revised over the past three decades and its operational functionality has been challenged, practical application based on this theory appears to have been made in the control of pain and itch using transcutaneous electrical nerve stimulation (Carlsson et al., 1975; Monk, 1993).

The clinical approach to pruritus can present a considerable diagnostic as well as therapeutic challenge. To formulate a simple clinical strategy for diagnosis and treatment of pruritus, pathological itch can be classified as primary or secondary (Table 11.2.1). Secondary pruritus is caused by either dermatological or systemic disease (Winkelmann, 1961; Winkelmann and Muller, 1964; Gilchrest, 1982; Bernhard, 1994). Pruritus can be further separated into localized and generalized forms based on the location and extent of body surface involvement. In most cases, localized pruritus is due to cutaneous infections or other regionalized expressions of dermatological disease. As a comprehensive classification to better understand the wide ranging causes and interventions for pruritus, The International Forum for the Study of Itch (<http://www.itchforum.net>) has adopted these broad categories: dermatologic, systemic, neurogenic, and psychogenic (Yosipovitch and Bernhard, 2013).

Generalized or diffuse pruritus typically presents more troublesome symptoms for the patient and a greater challenge for the physician. Diffuse pruritus is usually related to a dermatological or systemic disorder affecting the entire skin surface. However, even pruritus which is generalized or diffuse exhibits symptoms that may be accentuated and localized to certain regions of the body, and these symptoms may fluctuate, migrate, or extend over time.

Primary or idiopathic pruritus is identified in the majority (> 70%) of patients where dermatological disease (secondary pruritus) has been excluded as a cause for itching (Paul et al., 1987). Idiopathic pruritus may be fairly limited in extent and intensity. Symptoms can be reasonably controlled by conscientious skin care and topical soothing measures. However, other cases of primary pruritus prove to be quite extensive, severe, and chronic. The diagnosis of primary pruritus is established following a thorough medical and dermatological evaluation to exclude secondary causes of itching.

Evaluation and management of idiopathic pruritus is frequently a frustrating experience for the patient and physician as possible causes and beneficial treatments are sought. When no clear aetiology is delineated, both the patient and physician may experience disappointment. With severe idiopathic pruritus, there is also lingering uncertainty whether an occult disease, particularly malignancy, may eventually be uncovered. However, several clinical studies have shown that only a small percentage of patients referred to dermatologists for generalized pruritus will develop a malignancy during follow-up evaluation (Kantor and Lookingbill, 1983; Paul et al., 1987). The majority manifest haematological malignancies, particularly lymphomas, and therefore periodic clinical surveillance is warranted. However, the duration and severity of chronic primary pruritus may be sufficiently debilitating for palliative intervention and the identification of effective therapies to become the principal goals.

Secondary pruritus is associated with a variety of disorders including both dermatological and systemic diseases (Boxes 11.2.1 and 11.2.2). For example, contact dermatitis is a common characteristic skin disease that has itching and scratching as its hallmarks. Box 11.2.1 lists the major dermatological entities that are accompanied by pruritus. Some disorders, such as scabies, insect bites, folliculitis, and allergic contact dermatitis, are caused by exogenous agents that elicit pruritus. Other conditions, including atopic dermatitis, bullous pemphigoid, lichen planus, psoriasis, and urticaria, are endogenously mediated inflammatory skin conditions that exhibit variably intense symptoms of pruritus.

The mechanisms that induce itching have been partially characterized for some of these disorders. Specific inflammatory cell types, such as mast cells, lymphocytes, and eosinophils, play important roles in the pathogenesis of specific diseases and the development of pruritus. Neuropeptides, cytokines, and proteases, among other mediators, are the main cellular products initiating pruritus (Fig. 11.2.3). These mediators probably act in addition to specific neurotransmitters which directly convey a pruritogenic signal to the itch receptor. Treatment of the specific skin condition and elimination of any offending exogenous agent(s) typically alleviate the symptoms of pruritus. When dealing with pruritus which may be skin related, it is crucial to identify and classify any primary skin lesions and obtain appropriate skin sample specimens or skin biopsies. This information is often very helpful in establishing a diagnosis. The correct diagnosis and appropriate therapy for dermatological disorders should be sought through specialist consultation and is well described in standard dermatology textbooks.

Cutaneous diseases which cause pruritus should not be overlooked. For example, unrelenting pruritus caused by scabies infestation, sometimes lasting for months to years, has been mistakenly attributed to concurrent malignancy. Other cutaneous infections, irritant or allergic contact dermatitis, or autoimmune blistering diseases such as bullous pemphigoid have been repeatedly observed to develop during the course of malignancies or other systemic illnesses. By recognizing that pruritus is due to a supervening dermatological condition, prompt and appropriate treatment can be instituted and the skin disease and pruritus both resolve. Therefore the periodic evaluation and re-evaluation of the causes of idiopathic or poorly controlled pruritus may uncover new information that will significantly benefit total patient care and improve overall comfort.

Some dermatological conditions provide instructive lessons on the aetiology and limitations of managing pruritus. For example, prurigo nodularis is a distinctive pruritic dermatosis that can be chronic and is often recalcitrant to therapy (Doyle et al., 1979). The symptom of pruritus appears to play a more central role in the pathogenesis and propagation of this disease and there is increasing evidence that the primary form has a neurogenic aetiology. The pruritus of prurigo nodularis largely localizes to the nodular lesions that appear to develop and become more prominent as a result of scratching. Cutaneous nerve elements are accentuated and aberrantly located within the epidermis and dermis within the lesions and are often difficult to block effectively or eliminate. These factors probably account for the refractory nature of the condition to various treatments. Clinical and therapeutic observations on prurigo nodularis potentially have aetiological and practical relevance to non-dermatological disorders that are associated with pruritus since some of these conditions may also be quite refractory to many therapeutic measures directed at alleviating the itch.

Pruritus is a feature of a broad range of systemic diseases (Box 11.2.2). For some diseases, specific medical or surgical treatment provides cure of the illness and pruritus. However, with many of the chronic systemic diseases, patients may survive for long periods with adequate control of the illness. Unfortunately, pruritus often continues to be a major symptom and may cause considerable morbidity. Several excellent reviews have recently been published that examine the criteria and evidence to recommend various skin directed or parenteral agents for treatment of pruritus due to various systemic (systemic or neurogenic) causes (Weisshaar et al., 2012; Xander et al., 2013).

A variety of topical medications have been developed through the years to provide symptomatic relief of itching (Arndt et al., 1995; Devers and Galer, 2000). Many of the active ingredients have long been known to ease the symptoms of itch. A list of the common therapeutic antipruritic lotions, creams, and gels, together with their active ingredients, is given in Table 11.2.2. Topical medications are not convenient to apply to the entire body surface on a routine basis, but even patients with more generalized pruritus often have localized areas of accentuated itching that are more troublesome to control. Therefore topical agents have a role in treating both regionalized accentuation of generalized pruritus and localized itching.

Phenol in dilute solution (0.5–2%) alleviates pruritus by anaesthetizing cutaneous nerve endings. Phenol is potentially neurotoxic and hepatotoxic, and should be avoided in pregnancy and in infants under 1 year of age. Menthol and camphor relieve itching by counter-irritant and anaesthetic properties. Menthol (typically 0.25–2%, but can be as high as 16%) produces a cool sensation, and camphor (typically 1–3%, but can be as high as 9%) exerts similar effects. Zinc oxide, coal tars, calamine, glycerine, and salicylates also have been used in many preparations with reported benefit, although their specific modes of action have not been elucidated.

Pramoxine hydrochloride is a topical anaesthetic similar to dyclonine that has been used as the sole ingredient or has been compounded with hydrocortisone or menthol and is available as an aerosol, foam, cream, gel, or lotion. Newer anaesthetic prescription medications include EMLA™ cream, a combination of the caine drugs lignocaine (lidocaine) and prilocaine which are absorbed transcutaneously and produce anaesthesia as well as abolish itch. Lignocaine patches (Lidoderm^®) are also available that can be applied to problematic pruritic areas (Devers and Galer, 2000). Combinations of amitriptyline (1–2%) and ketamine (0.5–5%) compounded for topical application in solutions, gels, and creams have been shown to possess significant antipruritic and dysaesthesia-relieving activities when applied topically (two to five times daily) to limited (< 10%) body surface areas Poterucha et al., (2013a, 2013b). Doxepin has been demonstrated to be effective in relieving the itch of skin disease and may be useful for pruritus of various aetiologies. Capsaicin has been reported to be effective in localized neurogenic pruritus of various causes and has demonstrated benefit in other conditions accompanied by itch. Initial applications of the medication produce burning sensations and other discomfort. The patient must be alerted to these sensations and coaxed to continue if sustained use is planned and benefit is to be obtained.

A plethora of systemic medications and various other modalities have been used in the treatment of pruritus (Winkelmann and Muller, 1964; Gilchrest, 1982; Winkelmann, 1982; Denman, 1986; Fransway and Winkelmann, 1988; Lorette and Vaillant, 1990). These agents are organized and listed in Box 11.2.3 according to their standard pharmacological activities. On examining this list, it becomes apparent that no drug has ever been successfully developed, tested, and produced exclusively or even primarily for pruritus. This fact alone reveals the potential difficulties that are encountered in the pharmacological treatment of chronic and severe cases of pruritus. All too frequently, patients requiring palliative relief from intractable itching are subjected to trials of various medicines in an attempt to discover which one ‘works best’ for them. With persistence and luck, a particular drug or modality can be identified that offers benefit and has tolerable side effects. Combinations of systemic and topical agents often seem to provide the best relief. Clinical experience has also shown that certain medications or treatment modalities seem to provide more consistent benefit for specific types of secondary pruritus, as is the case for ultraviolet B (UVB) phototherapy and the pruritus of chronic renal failure. Unfortunately, few controlled clinical studies have ever been conducted on the palliative management of pruritus, and a well-developed and simple clinical management strategy does not exist. Therefore, as outlined above, the practical aspects of establishing the probable cause(s), selecting a treatment, and assessing its benefit, side effects, and potential risks must all be addressed routinely as part of the process of providing palliative care for the patient with pruritus. In addition, several simple measures can be adopted to give patients and their skin some relief from the anguish of itching and the injury of scratching.

Itching associated with malignancy presents special challenges and dilemmas. It can be among the most severe and recalcitrant forms of secondary pruritus. Patients with malignancy-associated pruritus represent a significant percentage of those requiring palliation, and many may manifest this symptom at some time during their illness. However, the frequency, chronicity, and severity of pruritus associated with malignancy and its response to treatment are difficult parameters to determine, and they have not been examined systematically and reported in the literature. For example, the percentage of patients for whom the symptoms of itching have been relieved by primary treatment of the malignancy versus those who have benefited from symptomatic therapies has not been defined in this population of patients. As a result, a single, specific, and effective treatment plan for pruritus of malignancy is not available.

Patients with itching of malignancy may manifest different types of pruritic skin lesions that warrant individualized therapies. Many patients will demonstrate excoriations due to scratching and injury of the skin from fingernails or other implements (brushes etc.). Other patients show discrete papular, crusted, or excoriated lesions more characteristic of prurigo. As a routine, close trimming and filing of sharp edges of fingernails as well as wearing cotton gloves, if necessary, are initial steps to minimize further skin injury. Tepid (not too warm or too hot) baths are usually soothing and temporarily relieve the itch. Patients often relate that a hot bath or shower feels more relaxing and offers symptom relief, but the itch is worse afterwards due in part to vasodilation and the accentuated neural response of cutaneous heating. Immediately following the bath and a light towelling, the patient or caregiver should lubricate the skin with a fragrance-free, cream-base emollient containing phenol or menthol if this is found to be beneficial. Applying a cream results in better maintenance of skin hydration and lessens the chance of further aggravation of pruritus from xerosis. Wearing clothing that is loose fitting, less irritating (e.g. avoid wools), and minimizes heat retention and sweating (e.g. avoid synthetics) can also be helpful in lessening the frequency and intensity of itch. Cotton fabric clothing usually meets these requirements.

For patients with numerous excoriations and crusting due to scratching, application of tap water wet dressings (or cotton long underwear soaked in water) to the affected areas several times daily for 1–2 h provides temporary relief and hastens healing of injured skin. A low- to medium-potency corticosteroid cream containing 1–2.5% hydrocortisone can be applied to the skin prior to the wet dressings for topical anti-inflammatory action. A more potent corticosteroid such as triamcinolone 0.05–0.1% in a cream base can be used for 7–10 days as needed on an intermittent basis, but prolonged use should be avoided to prevent atrophy and bruising of the skin, secondary skin infections, or hypothalamic– pituitary–adrenal suppression.

Various systemic anti-inflammatory agents are useful in the management of pruritus. Oral corticosteroids often improve the symptoms of itching for patients with primary or secondary pruritus. In many patients, the specific activity is unknown. The corticosteroid may inhibit release of pruritogens, inflammatory factors, or neuromediators, or it may block pruritogen activity or alter its metabolism. As with topical steroids, prolonged use has significant adverse side effects. However, in cases where the duration of treatment is limited, an oral corticosteroid can provide much sought relief of itching.

Antihistamines are another class of agent that offers benefit in treatment of itching. More than 30 different antihistaminic compounds of at least six different classes are available over the counter or by prescription. Although antihistamines provide minimal benefit for some patients with problematic itching such as that associated with Hodgkin’s disease, obstructive jaundice, or uraemic pruritus, they have a good safety profile and should be used at full dose to attempt amelioration of pruritus. For example, pruritus is an early manifestation of HIV infection, and antihistamines, sometimes at high dosages, are used to control symptoms. Studies have shown superior efficacy of sedating over low-sedating antihistamines for relieving itch. Low-sedating antihistamines (e.g. fexofenadine, cetirizine, and loratadine) should be reserved for the histamine-mediated whealing disorders that are accompanied by pruritus. Longer-acting antihistamines with central nervous system sedation are preferred for control of itch. These include chlorpheniramine, diphenhydramine, clemastine, hydroxyzine, and cyproheptadine. Agents of different classes should be tried if an antihistamine of one class is not effective. Sometimes, combination of agents from different classes is efficacious when a single agent is ineffective.

Cromones and thalidomide are anti-inflammatory agents that have been reported to be useful in pruritus associated with several different types of chronic or malignant disease. Disodium chromoglycate improves the flushing and pruritus of systemic mast cell disease (Soter et al., 1979). It also has been reported to improve the pruritus of Hodgkin’s disease when other therapies have failed (Leven et al., 1979). Thalidomide has been found to relieve the intractable pruritus and development of skin lesions in prurigo nodularis (Winkelmann et al., 1984). More recently, thalidomide (100 mg/day) was found to produce significant relief of uraemic pruritus (Silva et al., 1994). This drug is used primarily in the treatment of leprosy reactions and graft-versus-host disease. Because of its neuropathic and teratogenic side effects, thalidomide is not routinely available for prescription. However, selected patients who require only a limited course of therapy and can be monitored regularly may be candidates for thalidomide when an alternative medication is sought.

Many drugs have effects on the peripheral or central nervous system, and some of these agents have been found to be very useful in the treatment of itching from many causes. Anaesthetic agents administered by the intradermal, intravenous, or intra-arterial routes have effects similar to topical anaesthetics in blocking sensory input and transmission, including the sensation of pruritus. Parenteral lignocaine (200 mg in 100 mL saline by an intra-arterial line) alleviates refractory pruritus in hepatic cholestasis and chronic renal failure (Tapia et al., 1977; Levy and Catalano, 1985). Hypotension, cardiovascular effects, seizures, and psychosis are possible side effects. Recently, the anaesthetic sedative propofol, used at subhypnotic doses (15 mg) daily when itch was most severe or by continuous infusion at 1–1.5 mg/kg/hour, produced significant reduction in pruritus due to cholestatic disease of pancreatic neoplasia, hepatic and bile duct metastasis, cholangitis, and primary biliary cirrhosis Borgeat et al., (1993, 1994). A rapid onset of action within 5–10 minutes was observed. Propofol also relieves pruritus from spinal morphine administration, and it is postulated that propofol blocks effects of opioid-like pruritogens at the spinal level (Borgeat et al., 1992). Parenterally administered agents such as lignocaine, propofol, and naloxone are of relatively limited use in chronic pruritus. However, if acute severe episodes of pruritus become incapacitating, these agents can often provide much sought relief and re-establish some measure of symptom control.

Antidepressant drugs, including doxepin, amitriptyline, nortriptyline, and imipramine, have antihistaminic effects as well as psychoactive and analgesic properties that make them useful in the management of various pain and itch states. Serotonin reuptake inhibitors such as paroxetine have demonstrated significant activity in controlling recalcitrant types of pruritus, especially secondary to polycythemia vera (Diehn and Tefferi, 2001), as well as various other advanced cancers (Zylicz et al., 1998). Neuropathic pain with protopathic features of diffuse burning itch as well as the sensation of pain is improved by chronic antidepressant treatment (Willner and Low, 1993). These medications may also benefit patients with pruritus where depression appears to be playing a role in the prominence or severity of symptoms Fried, 1994). Neuroleptic medications, including pimozide and haloperidol as well as risperidone, drugs useful in the management of delusions of infestation (parasitosis), may play a therapeutic role in some clinical situations. Although not indicated for the primary treatment of organic pruritus, these agents may be useful when patients exhibit delusional ideation in conjunction with their disease process. Treatment improves the symptoms of psychosis and diminishes the mental fixation on pruritus (Fried, 1994).

Sedative medications such as diazepam have been shown to be ineffective in reducing experimental itch, although mechanically induced pruritus was eliminated with this agent (Hagermark, 1975; Lorette and Vaillant, 1990). Sedatives in conjunction with other antipruritic agents appear to offer greater relief if the patient is experiencing anxiety as part of the chronic pruritic reaction. In addition to the sedative effects of antihistamines such as hydroxyzine, doxepin, and diphenhydramine, specific anxiolytic agents, including buspirone, clomipramine, and benzodiazepines such as alprazolam, can be used when anxiety appears to be playing a role in magnifying the symptoms of pruritus. Long-term treatment with benzodiazepines should be avoided as there is a risk of habituation (Fried, 1994).

The opioid and serotonin antagonists, as reviewed earlier, have been found to be very effective in selected types of chronic pruritus. The opioid antagonists have been evaluated most extensively in the clinical setting of pruritus of cholestasis where they show significant benefit in symptom relief (Jones and Bergasa, 1990; Bergasaet al., 1995). Naloxone must be administered parenterally. Naltrexone and nalmephene are orally active agents which may be useful as longer-term therapeutic agents for chronic pruritus. Some studies have clearly demonstrated benefit for cholestatic pruritus (Jones and Bergasa, 2000), though randomized, blinded, and placebo-controlled studies in uraemic pruritus seem to indicate no significant improvement in symptoms (Pauli-Magnus et al., 2000). Serotonin (5-HT) antagonists are few in number and less well evaluated in pruritus. However, the 5-HT₃ receptor antagonist ondansetron shows promise as the first in a new class of agents to alleviate the symptoms of generalized pruritus in patients with cholestasis and chronic renal failure (Schworer and Ramadori, 1993; Raderer et al., 1994), although recent studies have refuted its efficacy in uraemic pruritus (Ashmore et al., 2000).

Gabapentin and the newer analogue, pregabalin are anticonvulsant drugs with analgesic activity but with no appreciable anti-inflammatory activities. These novel agents have recently been shown to bind to the alpha 2- delta-1 subunit of the voltage-dependent calcium channel and mediate analgesic properties in the brain and spinal cord levels. Both agents have activity in neuropathic pain, and recent clinical evidence indicates effectiveness in pruritus due to uraemic states as well as other types of primary and secondary pruritus, including pruritus following burn injury.

Sequestrants such as cholestyramine or charcoal administered orally or heparin administered by intravenous infusion have been reported to be helpful in the treatment of obstructive biliary pruritus (Fransway and Winkelmann, 1988). Cholestyramine was also observed to improve itching in polycythaemia vera and uraemia. These treatments may be useful as adjuvant or alternative therapies during the management of chronic pruritus due to these diseases.

A variety of miscellaneous therapies are listed in Box 11.2.3, which also includes additional disease-specific medications reported to benefit chronic pruritus and other treatment modalities such as phototherapy, transcutaneous nerve stimulation, plasma exchange, and acupuncture. Pertinent references reporting the benefit of specific therapies are cited for each modality. For example, several medications and physical modalities have been found to relieve the pruritus of chronic renal failure. Despite our lack of knowledge regarding specific pruritogenic factors and their expression and activity in chronic renal failure, UVB phototherapy often provides symptomatic relief. UVB phototherapy is well tolerated, has few side effects, and can be administered at many dermatological practices or regional clinical phototherapy centres. A combination of narrow-band UVB and crotamiton has been reported to alleviate pruritus of metastatic breast carcinoma to the skin (Holme and Mills, 2001). Erythropoietin and thalidomide have been reported to improve uraemic pruritus. Interferon-α and rifampicin have been found to be effective for polycythemia vera and malignant cholestatic pruritus, respectively (Price et al., 1998; Lengfelder et al., 2000). Parenteral lignocaine is typically reserved for severe recalcitrant episodes of pruritus in uraemic patients unresponsive to other measures.

The multitude and variety of medications and sundry other therapeutic modalities reviewed in this chapter attest to the magnitude, severity, and chronicity of pruritus. All these drugs and therapies have been successful, to some extent, in ameliorating or abolishing this troublesome symptom. In managing the symptom of pruritus as well as the disease, it behoves the physician to make the best possible assessment of the specific physical and emotional factors that may be contributing to the intensity and character of a patient’s problem of itch. With reassurance, flexibility, creativity, persistence, and a demonstrated concern by the physician, most patients will find relief and comfort.

Sweating is a physiological sudomotor response of skin that has pathological counterparts. Abnormalities of sweating can be classified in terms of quantitative or qualitative dysfunction. From the perspective of palliative care, the most troublesome sudomotor symptoms relate to inappropriate or excessive sweating which occurs as part of malignant disease or its treatment. To understand the aetiological factors contributing to abnormal sweating and its palliative management, the anatomy and physiology of the peripheral and central thermoregulatory systems of the human are presented and reviewed.

Sweating or perspiration is a unique function of the skin of humans and apes that allows evaporative heat loss and regulation of body temperature in a hot environment or during physical exertion. Other mammals must pant, seek a cooler location, rest, or splash the skin with water to lower body temperature thermally. The crucial function and efficiency of sweat production is witnessed in individuals with the inherited disorder anhidrotic ectodermal hypoplasia who are unable to rely on evaporative heat loss through sweating. Physical inactivity, a cool ambient environment, or wetting the clothing or skin with water substitutes for sweating in order to achieve thermoregulation. Another group of persons particularly susceptible to the adverse consequences of thermal stress are young infants and the sedentary elderly who fail to sweat sufficiently and are also more likely to develop and succumb to hyperthermia.

Sweating is an important component of the elaborate thermoregulatory system of humans that is shown diagrammatically in Fig. 11.2.4 (Ogawa and Low, 1992). The hypothalamus integrates inputs from central and peripheral thermoreceptors with the efferent response mechanisms, particularly sweating. The two types of thermosensitive neurons, warm-sensitive and cold-sensitive, are located in the preoptic and anterior hypothalamus (POAH). Warm-sensitive neurons respond to a rise in peripheral body temperature and are more abundant than cold-sensitive neurons which are activated by a decrease in peripheral temperature.

Body temperature is sensed at several crucial sites within the body, including specific thermoreceptors in the skin, spinal cord, and brainstem as well as thermal responses from the abdominal viscera. The POAH integrates thermal information from these sites and others in the body. Body temperature appears to be regulated to match a set-point. An abnormal upward shift of the set-point is believed to be the mechanism for production of fever. Additional control of the central thermoregulatory centre is mediated at several other sites in the brain with projections to the POAH, including the midbrain reticular formation, the raphe nucleus, the amygdala, the hippocampal formation, the sulcal prefrontal cortex, and the medial forebrain bundle. Thermoregulatory control of the hypothalamus can be modified by higher brain activity such as sleep, mental stress, and emotional excitement.

Hypercapnia, plasma osmolality, intravascular volume changes, and dehydration also alter the body temperature and set-point. Chemical mediators, including neurotransmitters such as catecholamines and acetylcholine and the eicosanoid prostaglandin E, play central roles in the control of normal thermoregulation as well as in the expression of fever. Hypothalamic peptides, including thyrotropin-releasing hormone, bombesin, neurotensin, adrenocorticotropic hormone, and vasopressin, are also important in the modulation of central thermoregulation.

The afferent input and efferent responses of thermoregulation are complex but are intimately coupled and controlled by both peripheral and central mechanisms (Fig. 11.2.5). The main thermoregulatory response affecting vasomotion and sweating is mediated through the autonomic system. The cutaneous vasculature is innervated mainly by adrenergic vasoconstrictor nerve fibres. Vasodilation and constriction are coordinated with sweating responses and interact to control blood flow and dissipate or preserve body heat. Sympathetic efferent pathways descend from the hypothalamus through the brainstem to the spinal cord and the preganglionic neurons. From here the fibres exit the cord and enter the sympathetic chain. Postganglionic sympathetic axons innervate sweat glands, blood vessels, and pilomotor muscles in skin. Eccrine glands are innervated by cholinergic fibres. Sweating is produced by both thermal and mental stimulation of eccrine glands, but the distribution and inciting factors causing the sudomotor response are different. Thermal sweating results from excess temperature that is perceived by the body. A local thermal stimulus will generate a uniform sweat response over the body surface while sparing the palms and soles.

The palms and soles show a baseline sweat pattern in the waking state, and mental excitement and stress will increase the rate. This response is called mental sweating. Mental sweating is controlled by the cerebral neocortex limbic system as well as by the hypothalamus. Thermal and mental sweating have some overlap in their central control but are also coordinated independently. General body surface sweating can be affected by various mental stresses. Mental sweating may augment or depress the thermal response of sweating over the body surface, but always increases sweating of the palms and soles. Axillary and, in some individuals, forehead sweating have a lower threshold to stimulation and are often active when there is no thermal sweating elsewhere.

Thermal sweating normally occurs uniformly over the body. Various factors, including body position, exercise, dehydration, sweat gland blood flow, ambient humidity, gender, and age, have also been shown to exert significant effects on the distribution, rate of production, activation thresholds, and other functional aspects of sweating. These factors must be taken into consideration in determining whether sweating responses are physiological or pathological.

In considering the palliative aspects of sweat dysfunction, most patients are typically bothered by hyperhidrosis (excessive sweating) or the distinctive symptom of nocturnal diaphoresis (night sweats) (Lea and Aber, 1985). A variety of underlying disorders contribute to localized or generalized hyperhidrosis (Table 11.2.3). Hyperhidrosis can be further classified as primary or secondary. It also should be appreciated that it may be a compensatory response to anhidrosis at other body sites. Therefore the cause of hyperhidrosis should be determined if possible, and attempts should be made to alleviate underlying abnormalities that may induce pathological states of excessive or insufficient sweat production.

Determination of sweating abnormalities can be based on the clinical history and examination, or on more comprehensive evaluations such as thermoregulatory sweat testing or specific measurements such as quantitative sudomotor axon reflex tests (QSART) (Fealey, 1992). QSART measures the pattern of sweat response and discriminates whether abnormalities in sweat production are pre- or postganglionic. Postganglionic abnormalities demonstrate alterations in the QSART while disturbances at the preganglionic level typically spare QSART function.

Thermoregulatory sweat testing assesses the integrity of the peripheral and central sympathetic sudomotor pathways (Fealey, 1992). Thermal stimulation is achieved by raising the skin temperature and the central or core body temperature. An environmentally controlled cabinet that warms the ambient air temperature to 45–50°C and also heats the skin with infrared lamps is used to raise central (oral or tympanic membrane) temperature and skin temperature to levels that stimulate sweating. Sweating on the skin surface is visualized with a special indicator powder containing iodinated corn starch, iodine solution, or alizarin-red-containing corn starch and sodium carbonate. Reduced or absent sweating can be delineated clearly (Fig. 11.2.5), and the distribution and extent of sweat loss is useful in further characterizing potential pathological abnormalities of the pre- or postganglionic pathways (Fig. 11.2.6) or the end organ, that is, the sweat glands (Fig. 11.2.7).

Disruption of the sympathetic chain or white rami produces localized loss of sweating as can be seen with a Pancoast tumour involving the apical lung (Fig. 11.2.6). In contrast, irritation of the sympathetic chain by encroachment of a neoplasm such as bronchial carcinoma, mesothelioma, or osteoma may also produce ipsilateral hyperhidrosis (Walsh et al., 1976). Stroke rarely causes contralateral hyperhidrosis if large infarcts affect both the superficial and deep cerebral structures. Basilar artery strokes have been known to produce focal symmetrical sweating.

Generalized hyperhidrosis occurs with various systemic diseases, including endocrine disorders, menopause, infections, lymphomas and other cancers, carcinoid syndrome, and drug withdrawal (Fealey, 1992). Endocrine disturbances observed to cause excessive sweating include acromegaly, diabetes mellitus, diabetes insipidus, hypopituitarism, hypoglycaemia thyrotoxicosis, and phaeochromocytoma. Drugs reported to cause hyperhidrosis include opioid analgesics such as morphine, diamorphine, methadone, butorphanol, and pentazocine, antidepressants such as fluoxetine, aciclovir, and naproxen. If patients experience significant symptoms of sweat excess as a result of a particular medication, switching to an alternative drug may provide significant relief. Although the mechanism producing hyperhidrosis is not clearly understood and may be different for each of these causes, a downward shift of the set-point of the POAH could stimulate inappropriate sweating.

The patient may confuse excessive regionalized sweating with generalized hyperhidrosis. Compensatory hyperhidrosis may occur within normal sweat-producing areas of the skin in response to anhidrosis that involves other areas of the skin. The patient may not notice the loss of sweating, but, rather, experiences discomfort from the exaggerated sweating response. In this case, detection of the underlying cause of the loss of sweating would guide further treatment and appropriate management for symptomatic hyperhidrosis.

The management of hyperhidrosis is based on identifying the primary cause underlying the abnormal sweat response as well as eliminating any potential aggravating factors that may further augment sweating. Primary hyperhidrosis will not be considered in the discussion of the palliative management of sweating. A variety of therapies offer benefit in treatment of primary hyperhidrosis but are not usually applicable to management of secondary hyperhidrosis (White, 1986). For primary localized hyperhidrosis, endoscopic thoracic sympathectomy or botulinum toxin injections into the affected skin regions are the most popular therapies (Heckmann et al., 2001; Vallieres, 2001).

Hot flushes are a prominent cause of excessive sweating in patients with cancer. A detailed discussion of the proposed pathophysiological mechanisms for this problem is outside the scope of this chapter, but can be found elsewhere (Casper and Yen, 1985; Charig and Rundle, 1989; Quella et al., 1994). Hot flushes classically occur in menopausal women and are associated with oestrogen depletion. Breast cancer survivors are not exempt from this clinical problem; in fact, they are more at risk for several reasons. First, adjuvant chemotherapy given to premenopausal women can frequently result in premature ovarian failure with all the sequelae of oestrogen-depletion problems; second the commonly used anti-oestrogen, tamoxifen, causes hot flushes as its most common toxicity; third, commonly used aromatase inhibitors also cause hot flushes; and fourth, general clinical practice has been to deny hormone replacement therapy to these women because of theoretical concerns that oestrogen replacement might harm them.

Given that breast cancer is a commonly diagnosed cancer whose incidence is rising, particularly among younger women, and that hot flushes are a very common clinical problem, what therapeutic options are available? Potential options can be grouped into two classes: hormonal and non-hormonal. Non-hormonal options will be considered first.

Twenty-five years ago, the most common non-hormonal treatment option for treating hot flushes was Bellergal^®. This is a mixture of phenobarbital and belladonna alkaloids. Review of studies, however, show minimal suggestions of efficacy for hot flushes (Bergmans et al., 1987).

Clonidine is the next non-hormonal agent that was studied and utilized for hot flushes. Well-conducted, placebo-controlled trials demonstrated that it reduces hot flushes more than does a placebo (Goldberg et al., 1994; Pandya et al., 2000). However, it only reduces hot flushes by about one hot flash per person per day, on average. It is also associated with toxicities, such as dry mouth, constipation, and sleeping troubles. Thus, it is not very useful for most women.

In the 1990s, data became available looking at the newer antidepressants as agents to decrease hot flushes. A placebo-controlled clinical trial looked at venlafaxine in a dose-finding study (Loprinzi et al., 2000). This demonstrated that venlafaxine, at a target dose of 75 mg per day (with an initiation dose of 37.5 mg per day), decreased hot flushes by about 60% from baseline, compared to a 27% reduction with a placebo arm. This agent does cause some toxicities, with nausea and vomiting being the biggest problem. In 5–10% of patients this is severe enough to prevent continuation of this medication. In the rest of them, however, the nausea generally abates with continuation of the drug for longer than one week.

Multiple additional antidepressants have been studied, illustrating that paroxetine Stearns et al., (2000, 2003, 2005), desvenlafaxine Deecher et al., (2006, 2007; Speroff et al., 2008; Archer et al., 2009), citalopram Barton et al., (2003, 2010), and escitalopram (Defronzo Dobkin et al., 2009; Freedman et al., 2011; Freeman et al., 2011; Carpenter et al., 2012) can decrease hot flushes to a similar degree as does venlafaxine. Fluoxetine and sertraline appear to also reduce hot flushes, but to a less substantial degree than is seen with venlafaxine and paroxetine (Loprinzi et al., 2002; Suvanto-Luukkonen et al., 2005; Kimmick et al., 2006). An individual patient pooled analysis confirmed that the available randomized trials demonstrated that antidepressants does decrease hot flushes (Loprinzi et al., 2009b).

There is concern that some of these antidepressants should not be used with tamoxifen as it interferes with an enzyme (CYP 2D6) which is utilized to convert tamoxifen to its active metabolite, endoxifen (Stearns et al., 2003). This concern was first noted with paroxetine. Fluoxetine also appears to be a strong inhibitor of CYP 2D6. Venlafaxine and citalopram have not been considered to be strong inhibitors of this enzyme, but are the topic of current investigation.

Subsequent to information regarding antidepressant use, data became available demonstrating that gabapentin also reduces hot flushes. At a target dose of 900 mg per day, it reduces hot flushes by about 50–60% (Guttuso et al., 2003; Pandya et al., 2005). An individual patient pooled analysis confirmed that the available randomized trials demonstrated that gabapentin does decrease hot flushes (Loprinzi et al., 2009b). An additional placebo-controlled trial demonstrated that a related agent, pregabalin, also decreases hot flushes to a similar degree (Loprinzi et al., 2010).

A recent trial compared the use of venlafaxine versus gabapentin in breast cancer survivors, in a randomized cross-over trial. This study revealed that the women preferred venlafaxine over gabapentin at a 2:1 ratio (p = 0.01) (Bordeleau et al., 2010).

There are other non-hormonal agents that have been studied, such as black cohosh and vitamin E, that do not appear to be very efficacious (Barton et al., 1998; Pockaj et al., 2006).

Soy products have been examined in multiple placebo-controlled clinical trials. The bulk of the information available suggests that soy is not very helpful for reducing hot flushes (Quella et al., 2000). There have been some studies which have reported positive results and, eventually, further investigation might define some soy product that does help hot flushes. Nonetheless, until this has been done, soy phytoestrogens should not be recommended as therapy for hot flushes.

Progestational agents, however, do clearly decrease hot flushes. A placebo-controlled trial examined 40 mg/day of megestrol acetate versus a placebo (Loprinzi et al., 1994b). This demonstrated an approximately 85% reduction of hot flushes, with low doses of megestrol acetate, results similar to what would be expected with oestrogen therapy. These results were replicated by an independent study group, which also supported that 20 mg/day was an effective dose (Goodwin et al., 2008). A subsequent clinical trial compared oral megestrol acetate to intramuscular medroxyprogesterone acetate (MPA) (Bertelli et al., 2002). Both of these agents appeared similarly advantageous, with a suggestion that the MPA was slightly better. Another trial compared a single intramuscular dose of MPA to continuous oral venlafaxine. MPA reduced hot flushes more substantially then did venlafaxine (Loprinzi et al., 2006).

There are hypothetical concerns with regards to the use of low doses of progestational agents in women with breast cancer (Loprinzi et al., 2006). There are some data to suggest that it might promote breast cancer growth, while there are other data suggesting that it might actually have antitumor activity. Many oncologists have been concerned about giving this therapy to women with a history of breast cancer, especially hormonal receptor positive breast cancer.

Oestrogen also decreases hot flushes by approximately 80–90% (North American Menopause Society, 2004) but increased concerns were raised with combined hormonal therapy (oestrogen plus progesterone) with the publication of the Women’s Health Initiative (Rossouw et al., 2002). This therapy increased the risk of breast cancer and increased the risk of cardiovascular trouble, including thromboembolic problems. This raised concern for the use of this therapy, both in women with breast cancer and women without a history of breast cancer. A subsequent Women’s Health Initiative trial reported on the use of oestrogen therapy alone (without a progestational agent) in women who had had a hysterectomy (Anderson et al., 2004). In this situation there was no increased risk of breast cancer, with a suggestion that there was actually a decreased incidence of breast cancer in women receiving Premarin^®, when compared to the placebo group. There are mixed reports with regards to the safety of oestrogen use in women with a history of breast cancer Vassilopoulou-Sellin et al., (1997, 1999, 2002; Dew et al., 1998; Col et al., 2001). All in all, oestrogen is frequently not utilized in patients with a history of breast cancer because of the concerns noted above.

Another group of cancer patients who suffer from hot flushes are men who have had androgen ablation therapy for prostate cancer. Hot flushes affect approximately 75% of such men and can be a very substantial problem (Charig and Rundle, 1989; Quella et al., 1994). Noting that there have not been near as many hot flash trials performed in men, as there have been in women, it has been proposed, as a general principle, that hot flash treatment in women can relatively well provide direction for what works in men (Loprinzi and Wolf, 2010).

Nonetheless, some hot flash studies have been done in men. A placebo-controlled trial demonstrated that clonidine does not appear to decrease hot flushes in men Loprinzi et al., (1994a, 1994b). A randomized, placebo-controlled, dose-finding, double-blinded clinical trial evaluated gabapentin for treating hot flushes in men, reporting results similar to what has been observed in women (Loprinzi et al., 2009a; Moraska et al., 2010). Additionally, pilot trials support that venlafaxine and paroxetine appear to help hot flushes in men as well as it does in women (Roth and Scher, 1998; Quella et al., 1999; Loprinzi et al., 2004). Lastly, low-dose megestrol acetate alleviates hot flushes in men as well as it does in women, with about an 85% reduction in hot flushes. It should be noted that megestrol acetate has occasionally been associated with rising prostate-specific antigen concentrations, however (Burch and Loprinzi, 1999; Sartor and Eastham, 1999). Therefore, it is reasonable to try one or more of the non-hormonal agents first, saving progestational agents for patients who do not get relief from non-hormonal agents.

Another cause of sweating is related to fever. Sweating is a physiological response to fever, and documented fevers that elicit diaphoresis either during or following the episodes need to be investigated and treated appropriately. Sweating can be a prominent clinical problem in patients with advanced cancer who have tumour fever. Antipyretic agents such as aspirin and paracetamol (acetaminophen) appear to reduce fever by resetting the POAH set-point, and these agents improve symptoms, including sweating, that are associated with fever. At times, however, patients with tumour fever are relatively asymptomatic while they are febrile, but they may perspire and chill during defervescence. A simple solution to this problem is to discontinue antipyretic medications. Asymptomatic fever may continue but symptomatic periods of defervescence decrease. Another method of treating tumour fever is to use non-aspirin-containing non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen. These drugs can be remarkably successful in alleviating tumour fevers and associated sweating (Chang and Gross, 1984; Tsavaris et al., 1990; Chang and Hawley, 1995). While the efficacy may cease after a period of weeks or months, switching to another NSAID may again induce defervescence (Tsavaris et al., 1990).

Sweating may be a chronic and prominent concern for many patients who do not have any malignancy or infectious aetiology. Even in patients with malignancy, where antipyretic therapies have either been instituted or discontinued to attempt symptom relief, diaphoresis may continue to be a major symptom. Various medications, including H₂-antagonists, have been tried empirically in attempts to provide relief. Although a specific mechanism of action is not well defined and documented clinical trials are lacking, clinical experience has indicated marked benefit from cimetidine (400–800 mg twice daily) in both idiopathic and malignancy-associated sweating. Whether other newer H₂-blockers exhibit a better or worse clinical response is not known.

Thalidomide is another medication that may exert significant benefit in reducing sweating as well as improving other symptoms and syndromes of advanced cancer, such as cachexia, nausea, and insomnia (Peuckmann et al., 2000). Both low-dose (100 mg orally every night) and high-dose (300 mg twice daily) thalidomide have been reported to improve sweating in the majority of affected patients (Deaner et al., 2000; Eisen, 2000). Thalidomide has been shown to reduce tumour necrosis factor-α production as well as modulate other interleukins and cytokines. Besides peripheral neuropathy, severe constipation, headache, cutaneous eruptions-skin sloughing, and oedema have been reported. However, the relative safety of the drug in advanced cancer favours judicious use. Other medications to be considered for management of excessive sweating in general as well as night sweats include thioridazine, nabilone, mirtazapine, desloratidine, and benztropine (Mold et al., 2012). It is hoped that improved therapies will follow as the peripheral and central neural controls of sweating become better understood.