methadone , a synthetic opioid agonist , is an effective alternative to strong opioids ( morphine , hydromorphone , oxycodone , and buprenorphine ) and is widely available for oral formulation . methadone has no known active metabolite and is part of the strategy of opioid rotation [ 19 ] . numerous studies suggest that the equianalgesic depends on the previous opioid treatment but there are few data on the use of intravenous ( iv ) methadone for the management of severe or refractory cancer pain [ 5 , 6 ] . cardiac toxicity is potentially of concern , especially because of the risk of arrhythmia ,  torsades de pointes  and sudden death [ 7 , 8 ] . we present our preliminary experience with iv methadone in 10 cancer patients with advanced disease and severe cancer pain already treated with high doses of opioids . ten consecutive patients with advanced cancer ( progressive disease ) were referred to our 12 beds unit for symptoms management and  intractable pain .  all had previously received various treatments for pain ( step i to step iii who ladder and various coanalgesics ) and were not controlled at the time of evaluation despite dose escalation or opioids rotation . they all presented with refractory pain and undesirable side effects from pain treatment and were considered at a palliative stage ( no more ongoing or planned chemotherapy , radiation therapy , or surgery ) . our criteria to introduce iv methadone were ( 1 ) advanced - severe cancer pain , ( 2 ) poor pain control with high doses of step iii opioids , ( 3 ) side effects from related pain treatment : dizziness , nausea , and myoclonus , ( 4 ) a neuropathic pain component , ( 5 ) no previous ineffective treatment with ( oral ) methadone , ( 6 ) no cognitive impairment ( capability to understand information ) , and ( 7 ) renal dysfunction . we used a 10  :  1 ratio from morphine to methadone in most cases . for other opioids morphine equivalent daily dose  ( medd ) before switching to methadone : morphine  :  hydromorphone : 7.5  :  1 , morphine  :  oxycodone : 2  :  1 , and morphine ( parenteral )  :  fentanyl ( transdermal ) : 80  :  1 . all patients had an electrocardiogram ( ecg ) to measure the qt interval before the introduction of iv methadone . a control ecg was planned once a week or according to clinical circumstances . in some cases , ketamine was considered if a breakthrough pain component was present ( it must be emphasized that fentanyl citrate is not available in belgium and there is no reimbursement foreseen ) . all continuous opioids ( not the rescue doses ) were discontinued four hours before starting iv methadone . pain was systematically measured with a visual analog scale ( vas ) , at t0 ( before to start iv methadone ) , t24 , and at the end of treatment . of course , pain was also evaluated every day by nurses and/or the medical team . other endpoints were adequate control of side effects , intravenous methadone tolerance , cognitive status , and cardiac toxicity . the median age was of 48 ( range 2064 ) for women and 49 ( range 4149 ) for men . all patients were already treated with high doses of opioids and two patients already had receive an association of hydromorphone and ketamine ( patient 1 and 10 ) . the median medd was 2400  mg ( range 450  mg6750  mg ) . five patients already received oral methadone ( patients 2 , 3 , 4 , 6 , and 8) . radiation therapy for pain management has been administered earlier in most cases without effective pain relief . all pain syndromes expressed a neuropathic component , essentially due to locoregional involvement , lumbosacral plexopathy , multiple bone metastases or leptomeningeal , and spinal cord involvement . all patients received iv methadone according to a converting ratio with the medd , with a median dose of 100  mg ( range 20400 ) . the median medd was calculated as 3000  mg ( range , 18012000 ) , and previous rescue doses ( hydromorphone , morphine , and oxycodone ) were taken into account when calculating the total dose of methadone . the final dose of methadone was higher in most cases despite a stable median of 100  mg ( range 25700 ) ( see table 2 for details ) . after 24 hours of iv methadone , all patients achieved a better pain control with a median of vas of 4/10 ( range 0/105/10 ) . the main reason was a breakthrough pain component ( from 2 to 4 episodes a day ) . our data show that intravenous methadone may be used for the treatment of severe cancer pain with a rapid pain relief , without unbearable side effect . because of the wide variation in the duration of treatment , we could not demonstrate long - term safety , although some of our patients received iv methadone for more than 20 days without toxicity . the use of methadone in the so - called  opioids rotation ,  is well established for years , essentially because there is no absolute cross - tolerance with the other types of opioids . the question of the equianalgesic dose ratio between methadone , morphine , and other opioids is not completely settled , particularly , in patients tolerant to high doses of opioids ; but there is an agreement to consider a ratio from 4  :  1 to 10  :  1 according to previous opioid dosage [ 19 ] . we adopted the 10  :  1 ratio , because the dosage of opioids was very high in all patients , prior to the switch to methadone . methadone has no active metabolites , is essentially excreted through the biliary tract , and can thus be used in cancer patients with renal function impairment . these potential advantages have to be weighed against relative risk of qt prolongation and the development of  torsades de pointes  potentially leading to fatal arrhythmias [ 7 , 8 ] . methadone has an antagonist action against n - methyl - d - aspartate ( nmda ) receptors , which are associated to the tolerance to opioids and also to the development of chronic pain . we had to resort to iv ketamine in 5 patients who presented with paroxystic painful episodes ; this suggests that the effect of methadone on the nmda receptors is only limited . the necessary dose of iv methadone remained stable in most of our patients . it is interesting that in 5 patients who were receiving methadone po , the iv administration improved dramatically the control of pain , maybe through a better biodisponibility of the medication . although it is generally accepted that the use of iv methadone requires a close medical monitoring , our results suggest that eventually the potential risks are not encountered very often and that , therefore , this therapeutic approach can be safely recommended for routine management of refractory pain in cancer . in conclusion , iv methadone is an effective pain relieving alternative for the treatment of severe cancer pain , especially in refractory pain syndromes , at the end of life . although the number of cases is small in this series , we did not observe any significant toxicity and the treatment was well tolerated with an effective pain relief . as our patients did not present any cognitive impairment during the treatment , it is likely that iv methadone might be an alternative to  terminal sedation ,  whichissometimes proposed to control refractory pain . further studies are necessary to confirm our data and to determine the right time to use iv methadone and its place in routine practice .
purpose . 
 methadone , a synthetic opioid agonist , is an effective alternative to strong opioids ( morphine , hydromorphone , oxycodone , and buprenorphine ) and is widely available as an oral formulation . 
 few data have been published so far on the use of intravenous ( i.v . ) 
 methadone for the management of severe or refractory cancer pain . methods . 
 we followed 10 consecutives cancer patients with severe pain , treated with iv methadone . 
 all had advanced disease and had already received strong opioids , some in association with ketamine . pain was assessed at t0 , t24 hours , and at the end of the treatment . 
 results . 
 all patients benefited from the switch to iv methadone with a reduction of pain on vas after 24 hours ( median : 4/10 ; range 05 ) until the end of the treatment ( all cases < 3/10 ) . 
 the median starting dose was 100  mg / day ( range 20400 ) and the final dose remained stable with a median of 100  mg / day ( range 27700 ) . 
 the median duration of iv methadone was 11 days ( range 259 ) . 
 no cardiac toxicity had been observed . 
 conclusions . 
 iv methadone is an effective pain relieving alternative for the treatment of severe cancer pain , especially in refractory pain syndrome . 
 moreover , we did not observe any toxicity ( neurological or cardiac ) or any other major side effects and the treatment was overall well tolerated . 
 more extensive comparative studies should be planned .