pain is a vital problem in cancer as it occurs in 3050  % patients in earlier stages and in 7090  % of these patients with advanced disease . the management of this symptom is generally based on the concept of the world health organization ( who ) analgesic ladder . this three - step framework was published for the first time in 1986 by the who to promote rational use of analgesic medications in the treatment of cancer pain . recent cancer pain management guidelines in europe are based on european association for palliative care ( eapc ) recommendations [ 2 , 3 ] . the knowledge of both basic types of pain ( nociceptive and neuropathic ) and their responsiveness to opioids is necessary to achieve good pain alleviation . medical data demonstrate that complete pain relief is rarely achieved in cancer patients ; nonetheless , it can be significantly reduced . to achieve better pain relief , apart from the use of the analgesics recommended by the who ladder , an appropriate application of adjuvant analgesics ( i.e. , for neuropathic pain ) , supportive drugs ( for the prevention and treatment of opioid adverse effects ) , and nonpharmacological measures such as radiotherapy and invasive procedures ( nerve blockades and neurolytic blocks )   should be considered and applied . certain data confirm some of the generally known rules , which are presented below . in patients with bone pain , opioids may be combined with nonsteroidal anti - inflammatory drugs ( nsaids ) and bisphosphonates along with local or systemic radiotherapy . neuropathic pain apart from opioid analgesics may require antidepressants , anticonvulsants , and local anesthetics . in patients with very severe neuropathic pain , the combination of opioids and n - methyl - d - aspartate receptor ( nmda ) antagonists , namely ketamine , is recommended . patients with visceral , colicky pain , especially in the course of bowel obstruction , should be treated with opioid analgesics and spasmolytics such as hyoscine butylbromide , hyoscine hydrobromide , or glycopyrrolate . their role in controlling cancer pain and other indications in the course of cancer and some practical aspects of steroid use will be discussed in this article . according to the who and eapc pain management recommendations , an adjuvant pain medication should be considered at each step of the who analgesic ladder , especially when the anti - inflammatory effect is needed . endogenous steroids , depending on their nature , site of synthesis , and specific clinical features , can be divided into four groups : corticosteroids ( glucocorticosteroids and mineralocorticosteroids ) , progestogens , androgens , and estrogens . generally , steroids are produced in the adrenals and gonads , and some other tissues such as the bowel , liver , prostate , and nervous system ( neurosteroids ) may synthesize or metabolize them . the principal sites of action and clinical consequences of corticosteroid excess are presented in table  1 . the knowledge of different corticosteroid properties is an important factor in the therapeutic decision making process . table  2 compares the most often used glucocorticosteroids with respect to the anti - inflammatory properties and the potency of sodium retention and the hypothalamic - pituitary - adrenal ( hpa ) axis suppression.table 1the principal sites of action of glucocorticoids in humans and some clinical consequences of its excesssite of actionconsequences of glucocorticoid excessbrain / cnsemotional liability , depression , insomnia , enhanced appetite , psychosiseyeglaucomaendocrine systemlh , fsh , tsh release , gh secretiongastrointestinal tractpeptic ulcerations , fatty livercarbohydrate / lipid metabolismoverall diabetogenic effectadipose tissue distributionpromotes visceral obesity ( cushingoid appearance)cardiovascular / renalsalt and water retention , atherosclerosis , hypertensionskin / muscle / connective tissueprotein catabolism / collagen breakdown , skin thinning , muscular atrophy ( myopathy ) , impaired wound healing , acne vulgarisbone and calcium metabolismbone formation , bone mass , and osteoporosisgrowth and developmentlinear growthimmune systemanti - inflammatory action , immunosuppressioncns central nervous system , lh luteinizing hormone , fsh follicle - stimulating hormone , tsh thyroid - stimulating hormone , gh growth hormone(adapted and modified from stewart ) table 2comparison of relative biologic potencies of different synthetic steroidssteroidsalt retentionanti - inflammatory effecthpa axis suppressioncortisol111prednisolone0.7534methylprednisolone0.56.24fludrocortisone1251212dexamethasone02617hpa hypothalamic - pituitary - adrenal(adapted from stewart ) the principal sites of action of glucocorticoids in humans and some clinical consequences of its excess cns central nervous system , lh luteinizing hormone , fsh follicle - stimulating hormone , tsh thyroid - stimulating hormone , gh growth hormone ( adapted and modified from stewart ) comparison of relative biologic potencies of different synthetic steroids hpa hypothalamic - pituitary - adrenal ( adapted from stewart ) the anti - inflammatory effect and vascular permeability reduction are the clinical results of steroid use . because the mineralocorticoid properties of steroids may lead to a higher risk of sodium excess , potassium loss , and water retention ( in such cases , a concurrent supplementation of potassium should be considered ) , cortisone or hydrocortisone are rarely employed for long - term anti - inflammatory therapy ( due to the highest sodium - retaining potency ) . the negative feedback of the hpa axis by endogenous and synthetic steroids is well established . clinically significant hpa axis suppression is rare if a steroid is administered for less than 3  weeks . there are some clinical situations ( i.e. , myopathy or dysphagia ) when steroids have to be discontinued even if they have been used much longer . the second is a combination of nonspecific symptoms of steroid withdrawal syndrome ( i.e. , lethargy , depression , anorexia , nausea , myalgia , or arthralgia ) . this syndrome must be distinguished from the suppressed hpa axis or relapse of the underlying disease . the third syndrome is acute adrenal insufficiency , which could be precipitated by surgery , intercurrent disease , or stress and may result in a hemodynamic collapse . after the glucocorticoid withdrawal , the hypothalamic and pituitary functions recover first , followed by the adrenocortical function . full recovery of adrenal function can take months , or even up to a year , especially after prolonged steroid treatment with high doses . a possible scheme of steroid discontinuation is presented in table  3.table 3the proposal schedule of glucocorticoid withdrawal when used over 3  weeksprednisone or equivalent daily doseproposal schedule of tapering 7.5  mgreduce rapidly , e.g. 2.5  mg every 34  daysthen57.5  mgreduce by 1  mg every 24  weeksthen < 5  mgreduce by 1 the proposal schedule of glucocorticoid withdrawal when used over 3  weeks ( adapted and modified from livanou et al . ) it consists of four stages : transduction ( in peripheral nociceptors ) , transmission ( via neurons ) , modulation , and pain perception . the possible role of steroids on every step of nociception has been raised even though the exact mechanisms remain unclear . the variety of proinflammatory cytokines synthesized or / and released during tissue injury are responsible for peripheral sensitization . the reduction in inflammation involved in this process decreases nociceptors activation , and thus , can diminish pain intensity . a decrease in pathological electrical activity of damaged neurons the anti - inflammatory effect of glucocorticosteroids results from their ability to inhibit the expression of collagenase ( the key enzyme involved in tissue degeneration during inflammatory mechanisms ) , reduce pro - inflammatory cytokines , and stimulate the synthesis of lipocortin ( blocks the production of eicosanoids ) . as a consequence , the reduction of peritumoral edema by the shrinkage of tumor in response to steroid therapy may lead to the improvement in analgesia in brain metastases   and spinal cord compression . the modulation of neuroimmune interactions by corticosteroids and the decrease of spontaneous discharge in an injured nerve may reduce neuropathic pain . the neurosteroids produced in the central nervous system ( cns ) or peripheral nervous system ( pns ) modulate the -aminobutyric acid ( gaba ) , nmda , and p2x ( for adenosine triphosphate or biphosphate ) receptors , which all play a crucial role in the regulation of pain . the receptors of various steroid hormones are expressed in several neural structures , allowing steroids to control the development , growth , maturation , differentiation , and plasticity of the cns and pns . by modulating neural activity and plasticity , sex steroids ( androgens and estrogens ) are key factors accounting for the gender difference in pain and analgesia . androgens , particularly testosterone , exert an analgesic effect in humans while estrogens were found to have both the hyperalgesic and analgesic effects , depending on the experimental conditions [ 19 , 20 ] . sex steroids in a rat model modulate the antinociceptive responses to opioids through the control of - and -opioid receptors in the spinal cord . long - acting dexamethasone causes less fluid retention than other steroids because it has less mineralocorticoid effect . however , betamethasone ( equipotent to dexamethasone ) , prednisone , and prednisolone also may be used . dexamethasone is metabolized by the hepatic enzyme cyp3a4 , and like other drugs metabolized in this way , it has numerous potential interactions . it may affect the metabolism of carbamazepine , tricyclic antidepressants , venlafaxine , dextromethorphan , and , to less extent , methadone . the effect of dexamethasone may be increased by cyp3a4 inhibitors and weakened by cyp3a4 inducers . corticosteroids are commonly prescribed in cancer patients for a variety of symptoms [ 24 , 25 ] . there is evidence for the use of corticosteroids for specific indications such as raised intracranial pressure , spinal cord compression , superior vena cava obstruction , and bowel obstruction . however , there has been little evidence for this in the literature with regard to hypercalcemia and nonspecific indications such as pain , nausea and vomiting , fatigue , cancer - induced anorexia - cachexia , depressed mood , or poor general well - being and dyspnea . the recommended dosing of corticosteroids in different clinical situations is presented in table  4.table 4corticosteroid doses for common indications in cancer patientsclinical indicationrecommended dose , mgspecificraised intracranial pressure816  mg dexamethasone dailyspinal cord compression1632  mg dexamethasone daily ( 816  mg b.i.d.)superior vena cava obstruction1624  mg dexamethasone daily ( 8  mg b.i.d or t.i.d.)bowel obstruction816  mg dexamethasone dailynonspecificanorexia4  mg dexamethasone ; 1020  mg prednisolonenausea and vomiting48  mg dexamethasonebone and neuropathic pain48  mg dexamethasone(adapted and modified from exton ) corticosteroid doses for common indications in cancer patients ( adapted and modified from exton ) corticosteroids display short- and long - term toxicities . the immediate adverse effects include immunosuppression , which may manifest as candidosis , hyperglycemia , and psychiatric disorders . long - term effects comprise myopathy , peptic ulceration , osteoporosis , and cushing s syndrome . therefore , due to a wide range of adverse effects , the lowest effective dose should be used . the combination of nsaids and steroids increases the risk of gastric bleeding 15-fold ; therefore , it should be avoided or gastroprotective drugs ought to be administered concurrently . bisphosphonates should be considered in the case of elderly patients and patients at risk of osteoporosis , especially when chronic steroid therapy is intended . due to the diabetogenic effect of steroids , all patients should be reviewed regularly to ensure that the treatment benefits outweigh the risks . in an uncontrolled study , oral candidosis and proximal myopathy were the most frequent adverse effects attributable to steroid therapy . a total of four ( 4  % ) out of the 106 treated patients discontinued the treatment due to adverse effects such as restlessness , sleep disturbance , dyspepsia , and skin rash . in another study , 181 ( 31  % ) out of 582 cancer patients experienced troublesome adverse effects . the most common adverse effects were moon face ( 43  % ) , myopathy / muscle weakness ( 34  % ) , skin purpura ( 31  % ) , oral candidosis ( 28  % ) , and aggravated or triggered diabetes mellitus ( 17  % ) . among 88 patients with brain metastases , the most frequently documented adverse effects of steroids were increased appetite ( 32  % ) , proximal muscle weakness ( 28  % ) , and insomnia ( 21  % ) . only 25  % of treated patients did not experience steroid - induced adverse effects . a comparison of prednisolone with dexamethasone showed that adverse effects of both drugs were similar , although more psychological changes ( p  <  0.02 ) and hyperactivity ( p  < 0.05 ) were observed in patients treated with dexamethasone . when comparing betamethasone with prednisolone , 33  % and 20  % of cancer patients , respectively , were assessed as having troublesome adverse effects . gastroprotectors were prescribed by 27  % of doctors to 75100  % of their patients treated with corticosteroids , and 65  % of physicians prescribed these drugs when patients received corticosteroids and nsaids concurrently . although hiccup is not a very frequent adverse effect of dexamethasone , in a recent case series , kang et al . [ 30 ] presented dexamethasone - induced hiccup that was easily resolved by switching to an equipotent dosage of either prednisolone or methylprednisolone . it is alkaline , so it is highly likely to be incompatible with acidic solutions . if dexamethasone is to be mixed with other drugs , as much diluents as possible should be added before the addition of dexamethasone . glycopyrronium chemically interacts with dexamethasone , but no precipitate forms ; therefore , this combination should be avoided . dexamethasone is compatible in mixtures with morphine , diamorphine , oxycodone , fentanyl , alfentanil , hydromorphone , dihydrocodeine , tramadol , hyoscine butylbromide , hyoscine hydrobromide , metoclopramide , and ondansetron . some uncontrolled studies reported benefits of corticosteroids on pain and symptom control in these patients . the issue of an appropriate steroid treatment is discussed in the literature , and many questions regarding this problem have been raised ( what are the exact indications for corticosteroid use ? how long are steroids effective in symptom management , including pain ? what is the most effective steroid dose ? nauck et al . , in a multicenter study carried out in 55 palliative care units in germany and one in austria and switzerland , established that corticosteroids were one of the commonly administered drugs and were administered to 33  % of those patients . corticosteroids were prescribed to 17.8  % of patients on admission and 32.4  % of patients during the stay at inpatient units . younger patients were treated more often with corticosteroids . in a more recent study conducted among 406 patients with advanced cancer who were consulted by a palliative care team in an outpatient clinic , corticosteroids were administered to about 25  % of patients . a retrospective observation of corticosteroid use at the end of life in hospice patients conducted by gannon et al . a total of 51  % of 178 patients received corticosteroids , which were continued until death in 53  % . the main indications included treatment for raised intracranial pressure and to give a  boost .  the foremost reason for discontinuation of steroids was loss of the oral route . conducted a randomized , double - blind , crossover study in 40 patients with advanced cancer . oral methylprednisolone , 16  mg twice daily , or placebo was administered for 5  days . then the patients were crossed over to the alternate treatment after 3  days of washout period . a total of 28 patients had pain of either bone , visceral , or neuropathic origin . visual analogue scale scores for pain and analgesic intake were lower in the case of the methylprednisolone treatment in all types of pain . the benefit disappeared after day 33 in one third of the patients . in a swedish survey , out of a total of 147 patients with pain , 50 ( 34  % ) had very good effect , 71 ( 48  % ) had some effect , 4 ( 3  % ) had no effect , and the effect of the treatment with corticosteroids could not be assessed in 22 patients ( 15  % ) . the positive response came within a week and lasted for more than 4  weeks . of these patients , 81  % used corticosteroids for more than 4  weeks and 90  % were on betamethasone , with daily doses less than 3  mg in most of the patients . della cuna et al .   reported a randomized double - blind study conducted among 43 patients with advanced cancer who were given either methylprednisolone , 125  mg intravenously daily , or placebo for 8  weeks . however , the follow - up study conducted among 173 women did not confirm analgesic effects of methylprednisolone . tannock et al .   reported an uncontrolled study of oral prednisone , 7.510  mg daily , in 37 patients with metastatic prostate cancer . greenberg et al .   reported an uncontrolled study of 83 patients with spinal cord compression and pain who received dexamethasone , 100  mg intravenously , followed by 24  mg orally four times daily tapered over the period of 2  weeks . pain relief was observed in 82  % of patients , in some patients before the commencement of radiotherapy . in an uncontrolled study , kozin et al .   demonstrated pain relief in 63  % of 64 patients with reflex sympathetic dystrophy . sturdza et al .   reported the use of steroids among oncologists and palliative care physicians in the management of patients with brain metastases . out of 38 physicians approached , 34 responded to this electronic survey ; 45  % routinely used dexamethasone , 4  mg four times daily ( 16  mg daily ) . the others determined the dose of steroid according to the presence or absence of neurological symptoms . the dose was tapered over 4  weeks following completion of the whole brain radiotherapy by 60  % of the physicians . hanks et al .   observed that dexamethasone showed tendency for better results than prednisolone in patients with pain due to compression of the nerve . a total of 16 out of 34 patients responded to the treatment : 8 ( 38  % ) out of 21 patients treated with prednisolone and 8 ( 62  % ) out of 13 patients treated with dexamethasone . however , this trend could have been associated with relatively higher doses of dexamethasone ( 4  mg daily , n  =  7 ; 8  mg , n  =  4 , 16  mg , n  =  2 ) compared with the doses of prednisolone ( 30  mg daily , n  =  10 ; 20  mg or less , n  =  11 ) . .   demonstrated effective use of corticosteroids in intractable bone pain in the course of hairy cell leukemia . vyvey [ 41 ] depicted a patient with a pancreatic carcinoid with metastases to the liver and spine and mixed bone and neuropathic pain . the patient was successfully treated with dexamethasone , 8  mg per day orally , which was subsequently reduced after a few days to the dose of 4  mg per day orally for 3  months . hardy et al .   conducted an uncontrolled study among 106 consecutive patients who started dexamethasone treatment according to the established prescription policy . the patients were surveyed each week to document the indications for use , beneficial effects , toxicity incurred and the reason for discontinuation of the treatment . all patients were diagnosed with advanced cancer and the median survival time was 40.5  days ( range : 1398  days ) from the start of dexamethasone treatment . the most common specific indications for treatment with dexamethasone were spinal cord compression , cerebral metastases , lymphangitis carcinomatosa , and bowel obstruction . the most common nonspecific indications comprised anorexia , nausea , low mood , pain , and vomiting . the median duration of steroid use was 21.5  days ( range : 189  days ) . symptom scores improved during the therapy compared with baseline in most patients for anorexia , nausea , pain , low mood , vomiting , and weakness , but not with respect to dyspnea and poor mobility . beneficial effects of steroid use on appetite , vomiting , general well - being , and social interaction in the dellacuna et al . the positive effect of steroids was seen by 71  % of physicians in poor well - being , 53  % in appetite loss , 45  % in nausea , and 40  % in fatigue . moertel et al .   reported a significant improvement in appetite in a randomized , double - blind , placebo - controlled study of dexamethasone in 116 patients with advanced gastrointestinal cancer after 4  weeks , although weight did not increase . strength was insignificantly improved , and performance status and survival were not different form control . the problem of appropriate steroid dose and its efficacy is raised in the literature and clinical practice . in a randomized double - blind trial vecht compared initial dexamethasone dose of 10  mg versus 100  mg in 37 patients with spinal cord compression who then received radiotherapy . lundstrm and frst   asserted that betamethasone ( equipotent to dexamethasone ) was the most commonly prescribed drug followed by prednisolone . the dose for the treatment of anorexia , fatigue , or low mood was betamethasone , 3.5  mg , or prednisolone , 17  mg . the mean starting doses for the treatment of nausea were 4.8  mg and 19  mg , respectively . the dose was tapered to maintenance dose if possible by 75  % of physicians ; 83  % stated that more than 50  % of their patients had a positive effect of the treatment , and 97  % of the respondents stated that the positive effect came within 5  days . hanks et al .   reported an uncontrolled study examining the effects of prednisolone or dexamethasone in 218 ( 58  % ) of a total 373 patients with advanced cancer admitted to the inpatient unit . the duration of treatment with corticosteroids varied from 1  day to almost 11  years ; the median duration was between 4 and 8  weeks . patients received either prednisolone ( n  =  121 ) or dexamethasone ( n  =  95 ) in starting doses of 1030  mg and 416  mg daily , respectively . the maintenance daily doses varied considerably from 520  mg of prednisolone and from 0.5  mg on alternate days to 4  mg twice daily of dexamethasone . the beginning and duration time of the clinical effect of corticosteroids is another unclear problem . in the swedish study , the authors noted that positive effect of steroids lasted from 3 to 6  weeks . of the questioned doctors , 83  % stated that more than 50  % of their patients had a positive effect from the treatment , and 97  % of the respondents observed the positive effect within 5  days . corticosteroids have an established role in specific indications in cancer patients such as spinal cord compression , superior vena cava syndrome , brain metastases with raised intracranial pressure and bowel obstruction . several studies suggest that corticosteroids may be effective in the treatment of bone and neuropathic pain , when administered along with opioids and with other adjuvant analgesics . the decrease in pain intensity is probably connected with both the anti - inflammatory and anti - swelling effects as well as modulation of neuroimmune interactions . it seems that dexamethasone may be commonly used for cancer pain management due to its high potency , long duration of action and minimal mineralocorticoid effect . a proposed starting daily dose is 8  mg ( orally , subcutaneously or intravenously ) with subsequent adjustment to the analgesia achieved and adverse effects . the lowest effective dose should be used and patients must be followed up regularly to assess benefits and risks associated with the therapy . in the situation when the general condition of a patient deteriorates and the patient is no longer able to swallow medications that are taken orally , it is rather recommended not to stop the treatment abruptly but to continue dexamethasone administration by the subcutaneous route . patients with severe pain intensity of bone and neuropathic origin should also be considered for the use of analgesic ladder step 3 opioids ( opioids for moderate to severe pain , strong opioids ) without climbing up the analgesic ladder . future studies that would take patients quality of life into consideration and could establish the role of corticosteroids in pain and other symptom treatment , are urgently needed .
pain is one of the most frequent and most distressing symptoms in the course of cancer . 
 the management of pain in cancer patients is based on the concept of the world health organization ( who ) analgesic ladder and was recently updated with the eapc ( european association for palliative care ) recommendations . 
 cancer pain may be relieved effectively with opioids administered alone or in combination with adjuvant analgesics . 
 corticosteroids are commonly used adjuvant analgesics and play an important role in neuropathic and bone pain treatment . however , in spite of the common use of corticosteroids , there is limited scientific evidence demonstrating their efficacy in cancer patients with pain . 
 the use of corticosteroids in spinal cord compression , superior vena cava obstruction , raised intracranial pressure , and bowel obstruction is better established than in other nonspecific indications . 
 this review aims to present the role of steroids in pain and management of other symptoms in cancer patients according to the available data , and discusses practical aspects of steroid use .