One of the big risks of methadone is in patients requiring these high doses. Methadone leaves the pain receptors before it leaves the body...so accumulation occurs, over time. Doses overlap and eventually a prolongation QT event may happen. When pain relief stops because the receptors open again, but the drug is still in you exerting effects elsewhere, raising doses becomes problematic.
Also people do vary in how they metabolize this drug. It can be very dangerous in really high doses, therefore.

Also switching high dose methadone from high Oxy use, increases risk of cardiac events. Most methadone given in a stepwise fashion, allows the body and its metabolism to deal with it more safely. Jumping in to massive methadone dose, can kill you. We had another poster at our old board die the first night on high dose methadone, switched from Oxy! (It was several years ago). She was a spinal/ back pain patient.