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Itch
Correspondence Address: Source of Support: None, Conflict of Interest: None
Although itch is a troublesome problem in many skin diseases and also occurs in some systemic disorders, it is a relatively unstudied and neglected symptom. Given that itch, like pain, is a pointer to an underlying disorder, and that cure or amelioration of the disorder will result in the resolution of the itch, it is understandable that physicians generally focus on identifying and treating the primary disorder rather than the secondary itch. However, when the causal disorder cannot be cured, patients can be left with a distressing, possibly intolerable, itch that significantly impairs their sense of well-being and quality of life.
Most physicians deal with the problem of itch simply by prescribing an H1-antihistamine. It is commonly believed that itch is caused by histamine release from mast cells in the skin and is treated with a topical and/or systemic H1-antihistamine. However, histamine release plays an essential role in only a few, usually acute, conditions such as urticaria, insect bites, and drug rashes. Thus, apart from the rare condition of cutaneous mastocytosis, low-sedative second and third generation H1-antihistamines [Table - 1] are of little or no value in chronic itch associated with conditions such as atopic dermatitis, psoriasis, cholestasis, uraemia, and lymphoma. In these circumstances, any benefit from a sedative first generation H1-antihistamine stems from a central effect distinct from peripheral H1-receptor antagonism.[1] Accordingly, it may be better to use a benzodiazepine, if only to help break the false association in the physician's mind between itch and histamine. It should also be noted that not all sedatives appear to be equally beneficial. In one study, nitrazepam was compared with butobarbital in relation to impact on nocturnal itch.[2] Although the subjective itch scores were more or less identical with both drugs, the total limb movements (suggesting scratching) were increased in patients receiving butobarbital but decreased when taking nitrazepam.[3]
The identification of a specific subset of unmyelinated C-fibres in peripheral nerves for the transmission of itch has transformed the scientific study of itch.[4] It is no longer possible to claim that itch and pain represent a sensory continuum, and that it is the intensity and/or the frequency of stimulation of peripheral nerves which determines whether a person experiences itch or pain. We now know that, although itch and pain share a common neuro-anatomical pathway, they are distinct phenomena [Table - 2]. Many endogenous chemicals are locally pruritogenic when injected into the skin, e.g. amines, proteases, growth factors, neuropeptides, opioids, eicosanoids and cytokines. [5, 6] Some of these chemical act by causing histamine release from local mast cells and/or by sensitising the relevant C-fibres. However, some stimulate the nerve endings directly, e.g. papain (a protease).[7] As with pain, the effects of peripheral pruritogens are modified by neuromodulators in the central nervous system (CNS). Thus itch induced locally by the intradermal injection of histamine in healthy subjects is diminished by both a peripherally-acting low-sedative H1-receptor antagonist (H1-antihistamine, e.g. cetirizine) and a centrally-acting opioid antagonist (naltrexone).[8] When itch is induced in volunteers by the intradermal application of histamine by injection or iontophoresis, functional positron emission tomography demonstrates co-activation of several areas in the brain with left-brain dominance.[9-11] The activation of multiple sites suggests that there is not an itch centre per se but, rather, an itch 'pattern generator'. Co-activation of the motor area matches the clinical observation that itch is closely linked to a desire to scratch. Although the patterns of activation for itch and pain are similar, there are important differences such as the absence in itch of detectable activation in the thalamus and the somatosensory cortex. Like pain, itch can be peripheral in origin (dermal or neuropathic) or central (neuropathic, neurogenic or psychogenic) (Box A[12-20]). Itch originating in the skin is 'pruritoceptive', i.e. induced by stimulation of the free nerve endings of the specialised C-fibres by one or more of a range of pruritogens. Neuropathic itch can originate at any point along the afferent pathway as a result of neural injury. [13, 14, 21, 22] Localised pruritus has been reported with peripheral nerve lesions such as notalgia paraesthetica (a sensory nerve entrapment syndrome involving the posterior rami of nerve roots)[15] and HIV T2 -T6 infection.[16]
Management can be considered under three headings:
Box A Classification of itch[12] Pruritoceptive itch Originates in the skin and transmitted to the CNS by a specific subset of C-fibres, e.g. dry skin, urticaria, rash, insect bites, scabies. Neuropathic itch Caused by injury to an afferent nerve or to the CNS, e.g. post-herpetic neuropathy (in addition to neuralgia), multiple sclerosis, brain tumour, brain abscess.[13-16] (Note: none of these is a common occurrence.) Neurogenic itch Originates in the central nervous system without organic neural pathology, e.g. hepatic itch,[17] opioid-induced itch[18] Psychogenic itch Originates in the mind, e.g. parasitophobia.[19] (Note: itch of any cause is made worse by the lack of distraction or by low mood.) Mixed type e.g. uraemia (pruritoceptive + neurogenic)[20] Box B Management of itch Correct the correctable treat the underlying cause apply emollient to dry skin stent obstructed bile duct modify dialysis regimen Non-drug treatment (general measures) light cool clothes cool humid environment tepid showers avoid alcohol and hot spicy food keep nails short Drug treatment Topical aqueous cream + menthol/phenol 1-2% topical antihistamines: only if itch is associated with histamine release polidocanol (e.g. E45 itch relief cream)a Systemic H1-antihistamines (if histamine-mediated) H2-antihistamines (if lymphoma) Opioid antagonists (cholestasis, uraemia?, other causes?) Ondansetron (opioid-induced) a. A non-ionic surfactant with local anaesthetic properties; also used in soya oil in uraemia As a general rule, it is pointless to apply topical drugs if the itch is neurogenic or neuropathic in origin. On the other hand, dry skin is generally an exacerbating factor in most patients with, for example, senile, hepatic, uraemic, or paraneoplastic itch. Thus skin care with an emollient should be considered basic treatment for all patients with pruritus. In relation to itch associated with the use of oral morphine in advanced cancer, even though the opioid effect per se is almost always central, other factors may well be involved and will influence management (Box C[23]). Box C Itch and oral morphine Likely to be multifactorial Dry skin High ambient temperature vasodilation and sweating Excipient in tablets? Morphine itself (central effect) Approach to treatment Emollient Cool environment Drugs diazepam 5mg o.n. and/or ondansetron 8mg b.d.[23] (Note: generally resolves spontaneously within 5-7 days.)
The next section is summarised in [Table - 3]. Because of a paucity of controlled trials in some areas, weight of evidence is not the only criterion which determines treatment choice. Absence of evidence from a controlled trial is not proof of lack of efficacy.
In controlled studies, both naloxone infusions[24-26] and oral nalmefene[27-29] have been shown to decrease scratching activity by patients with itch associated with cholestasis. Naloxone infusions have a potential place in the emergency treatment of acute exacerbations of the itch of cholestasis. [24, 25, 30] Naltrexone and nalmefene, which are both bio-available by mouth, can be used subsequently.[27-29, 31-33] However, orally administered opioid antagonists can precipitate a transient opioid withdrawal-like reaction in patients with cholestasis including hallucinations and dysphoria.[34-37] To avoid or minimise such a reaction, treatment is best started with a cautious infusion of naloxone, e.g. 0.002 mg/kg/min (about 160-200 mg / 24 h).[36] The rate of infusion can be doubled every 3-4h provided no withdrawal-like symptoms occur. After 18-24h, when a rate known to be associated with opioid antagonistic effects is reached (0.2 microgram/ kg/min), the infusion is stopped and naltrexone 12.5mg (1/4 of a 50mg tablet) t.d.s. or 25mg (1/2 of a 50mg tablet) b.d. is started. [35, 36] The dose is escalated steadily over a few days until a satisfactory clinical response is obtained. At this stage the effective dose should be consolidated into a single daily maintenance dose. The dose range for naltrexone is 25-250mg o.d.[36] Naltrexone is sometimes associated with hepatotoxicity.[38] The dose range for nalmefene is 25-120mg o.d.[27] Unfortunately, these drugs are not readily available in India.
Rifampicin is widely used for itch associated with intrahepatic cholestasis.[39] It is an inducer of mixed function oxydases and inhibitor of bile-acid reuptake from the gut. [40, 41] It was used in a placebo controlled trial in 9 patients suffering from pruritus of cholestasis for 2 weeks[39]. All patients reported significant reduction of pruritus after one week of treatment. The dose used ranged from 300-450 mg per day. By interrupting the enterohepatic circulation of bile acids, rifampicin may reduce the impact of increased bile acids on the metabolic processes of the liver. Rifampicin causes hepatic dysfunction in some patients, but the risk of this is reduced by starting with a low dose, e.g. 75mg o.d. If this is not effective after a week, the dose should be increased to 150mg o.d., and then to 150 b.d. Phenobarbital, another hepatic enzyme inducer, is also of benefit in a dose of 2-5mg/ kg/24h.[42] However, any benefit is probably the result of non-specific sedation, and it is now seldom used.
Colestyramine is an intestinally active anion exchange resin primarily licensed for the management of hypercholesterolaemia. However, by chelating bile acids in the intestines, it interrupts the enterohepatic circulation of bile acids. It has been used for many years to relieve itch in cholestatic disorders such as primary biliary cirrhosis.[43] Benefit has been claimed only in an open-label non-randomised long-term study of 27 patients.[44] Colestyramine is not effective in itch associated with complete large duct biliary obstruction because bile acids (and possibly other biliary pruritogens) do not reach the gut. When used, one 4g sachet is given before and one after breakfast so that the arrival of the resin in the duodenum co-incides with gall bladder contraction.[45] If necessary, a further dose can be taken before the midday and evening meals. The maintenance dose is generally 12g per day. However, many patients find it unpalatable and nauseating, and it commonly causes bloating and constipation. For these reasons it is seldom used in terminal cancer patients. If used long-term, it can cause malabsorption of fat-soluble vitamins.
The use of androgens to relieve pruritus in cholestasis stems from the serendipitous observation some 60 years ago in a patient with primary biliary cirrhosis whose itching cleared up when given an androgen for an unrelated reason.[45] Benefit is largely limited to 17α-alkyl androgens, e.g. norethandrolone, methyltestosterone and stanozolol,[46] possibly because of their greater bioavailability. Typical doses are: The manufacture in the UK of the first two drugs was discontinued many years ago, and stanozolol was withdrawn worldwide in early 2002. However, the antipruritic effect appears to be a class property, and benefit should be obtained with an alternative 17α-alkyl androgen, e.g. danazol, fluoxymesterone or oxandrolone. In women with a normal or long life expectancy, masculinisation (amenorrhoea, hirsutism and deepening of the voice) is a problem, but can be contained by reducing the dose of the androgen from daily to thrice weekly or even less.[46] 17α-alkyl androgens are directly toxic to hepatocytes.[47] It is possible that the effect of androgens like methyltestosterone and stanozolol is mediated via focal hepatocellular damage, thereby limiting the ability of the cholestatic liver to produce enkephalins.[48] Certainly, androgens themselves can cause cholestatic jaundice and have occasionally caused serious liver impairment.[49] This is clearly a potential problem for patients with a prognosis measured in years, e.g. those with primary biliary cirrhosis. However, now that orally administered opioid antagonists are available, the use of androgens has been largely superseded, except perhaps in patients taking opioid analgesics for pain relief in advanced cancer. In such patients, a trial of a 17α-alkyl androgen for 7-10 days is warranted.
Enhancing the dialysis regimen is the standard response when dialysis patients experience itch. Parathyroidectomy may result in a remission of itch in patients with secondary hyperparathyroidism and hypercalcaemia.[50] In other circumstances hypercalcaemia is not associated with itch.
Ultraviolet B therapy, particularly narrow-band UVB, is effective in many patients,[51] and may be superior to drug therapy. [52, 53]
Two randomised placebo-controlled double-blind studies of naltrexone 50mg once daily have been reported. [54, 55] Both used VAS as a subjective measure of itch, both recruited only a small number of patients (15 and 23 respectively), but the results were contradictory; one showed benefit, the other did not. In the positive outcome trial (benefit with naltrexone), the patients had initial VAS scores of 90-100 mm, whereas in the negative outcome trial the mean initial VAS scores were some 50-60 mm. It is possible, therefore, that naltrexone is of benefit only in very severe uraemic itch, when a disturbance in the balance of μ-and \?\-opioid receptors could become a prominent causal or exacerbating factor.[56] Thus, until further data is available, it seems reasonable to offer a trial of naltrexone to uraemic patients with severe uncontrolled itch, possibly increasing the dose progressively to 250mg/day (as in cholestasis) if 50mg/day does not suffice.
Thalidomide is effective in over 50% of patients with uraemic itch.[57] However, because of its history of causing severe congenital abnormalities, thalidomide is unlicensed and therefore not readily available. Thalidomide can also cause peripheral neuropathy. In those who are sexually active, strict contraception must be observed. It should be used only when other measures have failed.
The use of α-interferon as a cytoreductive agent in polycythaemia vera is associated with amelioration of itch. [58, 59] Itch in polycythaemia vera responds poorly to H1-antihistamines but often responds well to paroxetine.[60] However, the drug of choice is low-dose aspirin; 300mg is generally effective within 30 minutes with a duration of action of 12-24 hours.[61-63] Because platelet degranulation is increased in polycythaemia vera (releasing serotonin and prostanoids) and is known to be decreased by aspirin, the antipruritic effect of aspirin could be related to its impact on platelet dynamics.[61] Curative radiotherapy and/or chemotherapy is obviously the best approach in Hodgkin's lymphoma. Corticosteroids often relieve itch in late-stage Hodgkin's lymphoma, although the mechanism of this effect is unknown. In the past some patients obtained benefit with α-interferon,[64] but this treatment is no longer used. Paroxetine appears to be ineffective in Hodgkin's lymphoma (Zylicz et al. personal communication) However, case reports suggest that cimetidine, an H2-receptor antagonist, 800mg-1g daily in divided dosage may be beneficial.[65] It may also be of benefit in polycythaemia vera.[66] The antipruritic effect is possibly related to inhibition of hepatic cytochrome CYP2D6 rather than to specific H2-receptor antagonism.[67]
Paraneoplastic itch associated with solid tumours is not eased by corticosteriods or cimetidine. However, paroxetine is almost always beneficial, often within 24 hours.[68]
H1-antihistamines are ineffective for generalised opioid-induced itch caused by spinal opioids. Bupivacaine added to spinal opioids tends to restrict itch to just the face.[69] Pretreatment with a non-steroidal anti-inflammatory drug (NSAID), either rectal diclofenac 100mg or intravenous tenoxicam 20mg, has been shown to reduce the incidence, intensity and duration of itch in surgical patients receiving spinal opioids. [70, 71] These patients also had significantly less pain than control patients and needed significantly less postoperative opioid analgesia. It is possible that the difference in opioid dose may explain the difference between the two groups. 5HT3-receptor antagonists, e.g. ondansetron 4-8mg intravenously, may also be beneficial.[23] In 100 patients treated in a randomised controlled trial, relief was rapid and complete, generally within minutes. However, it is unclear whether this effect is maintained. Naloxone abolishes itch induced by spinal morphine but sometimes also reverses analgesia.[72-74] Itch associated with systemic morphine is similarly abolished. Naltrexone is also effective.[75] Nalbuphine, a mixed μ-opioid receptor antagonist and \?\-opioid receptor agonist, is more effective than naloxone and does not reverse analgesia.[76] Opioid-induced itch is rare in palliative care; because the few patients who receive spinal opioids and those who do are not opioid-naïve. Further, such patients almost always receive bupivacaine concurrently. When itch is induced by systemic morphine and persists for more than a week, switching to an alternative such as buprenorphine or tramadol may help.[77]
The HIV/AIDS pandemic in Sub-Saharan Africa, many parts of Asia, and several other countries has caused major health and socioeconomic problems. Health services, already under-resourced and over-stretched, are faced with very difficult decisions about resource allocation. Thus, in many countries, the Government has not sanctioned the routine use of antiretroviral drugs for people with AIDS. Apart from the adverse effect this must have on the course of AIDS and its outcome, it means that specific symptom relief will generally be all that can be offered. In people who are HIV-positive, itch is common. It can be associated with dry skin and with several skin diseases, including atopic dermatitis, psoriasis and scabies, as well as with organ impairment or neoplasia. Further, in those with a CD4 count below 300/ microlitre, eosinophilic folliculitis may occur on the upper half of the body.[78] This is an intensely pruritic eruption with urticarial papules, plaques or pustules associated with a raised plasma IgE concentration. Others who are HIV+ experience severe itching without an obvious rash or eosinophilia. It is possible that in some of these the cause may be neuropathic.[79] Sometimes, an NSAID is of benefit[80] but frequently the itch remains intractable. As always, 'necessity is the mother of invention' and, in the absence of antiretrovirals and cost disincentives in relation to drugs such as fluconazole (for candidiasis), herbal remedies are being rediscovered or newly recognised, though not yet scientifically evaluated (Box D). Box D Topical herbal application for itch Ingredients Centella asiatica Bulbinella natalensis Bulbinella frutescens Lippia javanica If associated with scabies or ringworm, add Flowers of sulphur
Despite the need for effective remedies for itch, the likelihood that the pharmaceutical industry will invest billions of dollars in the search for effective non-sedative centrally-acting antipruitics is surely zero. Given the relatively small numbers involved, such a project would not be commercially viable. This means that effective drug treatment for itch will always be a 'spin-off' from a drug developed and licensed for some other condition. Clinical interest in a drug is likely to be aroused as much by serendipity or co-incidence as by considered pharmacological judgement. So, itch is likely to remain a Cinderella symptom. However, we can hope that clinicians will take this relatively neglected symptom under their wing, and show determination and imagination in providing physical relief and psychological support for those who suffer from chronic itch associated with an underlying incurable condition.
[Table - 1], [Table - 2], [Table - 3]
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