Although the use of oral analgesics for the control of cancer pain has been demonstrated to be successful in most patients, some patients will fail to respond to pharmacological therapy or will suffer unacceptable adverse effects. Experience is accumulating that when adverse effects prevail with oral opioid administration, the analgesic response may be improved by changing the drug and/or the route of administration. Switching to an alternative opioid may further improve the balance between analgesia and adverse effects. Despite optimal systemic opioid treatment, in some complicated circumstances it is necessary to find different solutions, including the neuraxial administration of multiple drugs with different characteristics, which are difficult to manage. Three case reports illustrate how complex could be the analgesic approach using multiple analgesic regimens and different routes of administration to effectively manage complex pain syndromes commonly defined as unresponsive.