this is not only because pain is one of the most predominant symptoms in cancer patients but also because there is a wide range of pathophysiological process that causes pain , which needs a comprehensive assessment and specialized management strategies . it is well documented in the literature that effective pain management does not only improve a patient 's quality of life but it also significantly improves overall survival in cancer patients . therefore , it is imperative to realize that manifestation of pain in a patient with a life - limiting illness can have a number of underlying pathophysiological dysfunction including physical , psychosocial , and spiritual aspects . therefore , a comprehensive / multimodality approach toward pain management can be conceived to be intuitively more effective than unimodal approaches , such as pharmacotherapy . a comprehensive review of different pain management strategies is beyond the scope of this case study ; however , this case highlights the different aspects of manifestation of pain and the challenges that were faced in managing it effectively . some of the recent thoughts and evidence ( or the lack of it ) of ketamine and methadone in cancer pain management are also briefly reviewed . a 25-year - old male , with known family history of hereditary nonpolyposis colon cancer , was diagnosed with a de novo stage iv ( t4n2m1 ) transverse colon cancer on surveillance colonoscopy and underwent a total colectomy and partial hepatectomy . four of 27 resected lymph nodes were positive for tumor deposit ; the tumor was ras and braf mutant . he did not have any other known medical condition at the time and was not on any regular medication . he was a current smoker with 10-pack - year smoking history and also smoked marijuana on a regular basis , but did not report using any other recreational drug in inhaled or injectable forms . although born to catholic parents , he did neither identify himself to be a strong believer in religion nor claim to be an atheist . at the time of diagnosis , the patient was living independently at his home with his girlfriend . the patient underwent 5 cycles of adjuvant chemotherapy with folfox ( 5-fu , leucovorin , and oxaliplatin ) , but unfortunately developed disease progression 3 months after initial diagnosis , with the development of right femoral , adrenal , and nodal metastatic disease . the chemotherapy regimen was changed to folfiri ( 5-fu , leucovorin , irinotecan ) , and the patient underwent prophylactic intramedullary nailing of the right femur to prevent pathological fracture , followed by radiotherapy to the same area . the patient reported gradual onset , constant , dull pain in the right inguinal and thigh area . this bony pain correlated to the known metastatic site in the right femur and was partially helped with the palliative radiotherapy . the patient , who was opiate nave at the time , was commenced on long - acting oxycodone 10 mg bid with the immediate release of oxycodone 5 mg as breakthroughs with good clinical efficacy . three months after commencing second - line chemotherapy , the patient developed further progression of the disease as evidenced by new bony metastatic sites including right iliac crest , left femoral neck , and sacral ala as well as widespread liver metastases . he underwent prophylactic intramedullary nail insertion of the left femur followed by radiotherapy and an increase in his analgesic regimen with variable effects . over the following 3 months , the patient 's bony pain became a significant issue with multiple painful sites secondary to bony metastases which needed an escalation of his opioid doses by his medical oncologist , from long - acting oxycodone dose of 20 mg bid to ultimately 160 mg bid along with single fractions of palliative radiotherapy to the painful sites with partial but short - lived benefit . nine months after original diagnosis , the patient presented to the hospital with an acute pain crisis and this is when the patient was referred to the hospital palliative care team . the pain , as described by the patient , was widespread over multiple bony sites with a fluctuating pattern of intensity . the patient was mostly wheelchair bound at this stage as minimal amount of movement / weight - bearing seemed to exacerbate the pain . an increasing amount of oral breakthrough usage did not seem to alleviate the pain as reported by the patient . the patient also showed a significant amount of anxiety , frustration , and despair regarding the fact that his disease was progressing with no meaningful response to anticancer therapy . the patient felt that his increasing pain was a manifestation of his worsening disease status . on review , first , a pattern of early satiety and postprandial vomiting in the patient was noted , which , on investigation by barium swallow and gastric emptying studies , was confirmed to be gastroparesis ( possibly related to platinum drugs in the chemotherapy regimen ) , suggesting that poor absorption of oral long - acting opioid drugs was contributing to poor pain control . second , opioid tolerance was postulated to be contributing toward poor pain control , and finally , it was felt that the patient had significant existential distress , possibly manifesting as a pain syndrome . with these working hypotheses , the acute pain crisis was managed by stopping all oral opioid analgesics and commencing the patient on regular 4 hourly subcutaneous hydromorphone including hydromorphone breakthroughs , and doses were up - titrated until an acceptable level of pain control was achieved . a therapeutic trial of dexamethasone 8 mg / day the delivery method of the analgesics was then changed to a continuous subcutaneous infusion through a syringe driver with 110 mg hydromorphone over 24 h with the provision of 15 mg as breakthroughs as a subcutaneous injection . although this controlled the patient 's pain optimally for 4 weeks , the pain became resistant to it again being evident by an increasing number of breakthroughs required in any given 24-h period ( ranging from 12 to 20 breakthroughs ) . at this stage , in the absence of other therapeutic options ( the patient had already exhausted radiotherapy options and an intrathecal block was deemed unacceptable to the patient ) , ketamine was added to the analgesic regimen . he was commenced on 300 mg of ketamine over 24-h through the syringe driver with 2 mg haloperidol to counteract the neuropsychiatric side effects with modest clinical improvement in pain control . the ketamine dose was further increased to 500 mg/24 h in the following 2 weeks with ongoing clinical benefit . interestingly , this clinical improvement of pain control was also short - lived with further precipitations of pain crisis , when the ideas of disease progression , opioid tolerance , opioid - induced hyperalgesia , and psychosomatic aspects of pain manifestations were all considered and discussed with the patient . low - dose methadone at 10 mg bid was added to the pain regimen at this stage with the dose increased up to 30 mg tds with moderate therapeutic benefit . throughout the entire duration of palliative care team 's involvement , other allied health professionals were invited to the case management , including clinical psychologist , social worker , and occupational therapist . although the patient was receptive of the recommendations and suggestions of these teams in his overall management plan , he remained mostly reliant on his girlfriend for psychosocial support . the patient 's final hospital presentation was due to a combination of disease progression , progressive functional decline , and psychospiritual distress , which remained difficult to manage despite a concerted effort by palliative care , medical oncology , clinical psychology , and allied health teams . ketamine hydrochloride is a dissociative anesthetic agent , commonly given intravenously or intramuscularly for surgical anesthesia . during the last decade , it has become apparent that low , subanesthetic doses of ketamine may improve opioid analgesia and has been widely used off label as an adjunct to opioid agents for poorly controlled cancer pain . ketamine is a noncompetitive n - methyl - d - aspartate ( nmda ) receptor antagonist . it interacts with nmda receptor complexes , interrupts cholinergic transmissions , and inhibits the reuptake of noradrenaline and 5-hydroxytryptamine . there is good evidence from experimental animal models , human volunteer studies , and small clinical trials that nmda receptor antagonists relieve some types of neuropathic pain . however , their use is restricted by unpleasant adverse effects , including cardiac ( hypertension and tachycardia , especially of concern in patients with ischemic heart disease ) and neurologic ( e.g. , hallucinations , a sense of disconnection , vivid dreams ) . there is also emerging evidence on the deleterious effect of ketamine on bladder function . the nmda receptor also seems to play a role in the development of opioid tolerance . ketamine in low doses ( e.g. , 1 mg / kg/24 h as a subcutaneous infusion ) has been suggested to reverse or partially reverse opioid tolerance . there has been a general paucity of high - level clinical evidence of efficacy of ketamine in managing cancer - related pain . evidence to support the use of ketamine in chronic cancer pain has mostly been extrapolated from other settings and has been justified primarily from case series and uncontrolled studies . a randomized , controlled trial , although not in cancer pain , also reported the lasting effect of a single ketamine infusion in patients with ischemic pain . two randomized control trials of sufficient quality have also returned broadly positive conclusions . on the contrary , a recent , well - powered , randomized , double - blind placebo - controlled study to assess the efficacy and toxicity of ketamine in the management of cancer pain concluded that no net clinical benefit exists for ketamine in this setting . although this is a major finding to refute the role of ketamine in cancer pain management , it is unlikely to influence the current clinical practice unless the results are reproduced in further well - designed , robust studies . therefore , although the evidence base for ketamine as an adjuvant to opioids for cancer pain remains weak , the available literature allows for a cautious conclusion that there is a promise in the potential efficacy of ketamine as an adjuvant to opioids for cancer pain . methadone is a lipophilic and highly protein bound synthetic opioid with a 50%80% oral bioavailability and a half - life of 72 h. methadone has many attractive features as an analgesic , such as the high bioavailability , lack of known metabolic products that produce neurotoxicity , and multiple receptor affinities . not only methadone has activity at the mu - opioid receptor but also it is an inhibitor of serotonin reuptake and a moderate antagonist at the nmda receptor . these properties have raised interest in using methadone for neuropathic pain as well as for opioid tolerance and opioid - induced hyperalgesia . the pharmacoeconomic benefit of methadone has also prompted a reappraisal of this medication since it is much less costly than proprietary sustained - release opioids . however , methadone undergoes n - demethylation through the cytochrome p450 group of enzymes to such a variable extent that there can be interindividual variability in steady - state serum levels . thus , there are multiple potential drug interactions with medications commonly employed in pain management . there is also potential instability in methadone 's effects related to variability in protein binding , excretion , and equianalgesic potency . the most significant risk of parenteral administration of methadone , which is unique to this medication , is qt prolongation , which can lead to potentially fatal arrhythmias including torsades de pointes . close monitoring is especially needed in the presence of other risk factors such as electrolyte abnormality , structural cardiac disease , or some congenital diseases . all of these have led to a divergence between the supporters and critics of methadone utilization . while morphine has long been the  gold standard  by which other opioid analgesics have been compared , methadone has been proposed as a suitable alternative because of its lower potential for opioid - induced neurotoxicity , absence of active metabolites , and nmda - receptor - antagonist activity . unfortunately , this concept has not been widely studied , and a recent systematic review only found two studies comparing methadone to morphine and transdermal fentanyl , which showed comparable efficacy but increased toxicity and dropout rates for methadone . the evidence , however , was considered poor based on the quality of the studies and inconsistent results . recent data support the conclusion that s - methadone ( d - isomer ) , by virtue of its nmda - receptor - antagonist activity , affects the development of morphine - induced tolerance and hyperalgesia . using animal models of neuropathic pain , davis and inturrisi examined the ability of s - methadone to attenuate the development of morphine tolerance and to modify nmda - induced hyperalgesia . administration of intrathecal s - methadone reversed tolerance induced by intrathecal morphine . in a related series of experiments , these investigators demonstrated an s - methadone - mediated reduction in hyperalgesia following administration of nmda by d - methadone . these results support the inhibitory effect of s - methadone on the development of morphine tolerance as a result of its nmda - receptor - blocking activity . notwithstanding , there remain limited clinical data relating to methadone 's potential advantage in treating neuropathic pain , hyperalgesia , and tolerance . thus , its potential role in these conditions remains a compelling concept that requires further investigation . methadone may be ideal for those patients with renal impairment as it does not accumulate in renal failure and is insignificantly removed during dialysis . because of its intrinsic extended analgesic effects , methadone may also have an advantage over sustained - release formulations in those with rapid bowel transit times or in those with  short gut syndrome .  unfortunately , the dosing frequency required in such cases is unclear . ketamine hydrochloride is a dissociative anesthetic agent , commonly given intravenously or intramuscularly for surgical anesthesia . during the last decade , it has become apparent that low , subanesthetic doses of ketamine may improve opioid analgesia and has been widely used off label as an adjunct to opioid agents for poorly controlled cancer pain . ketamine is a noncompetitive n - methyl - d - aspartate ( nmda ) receptor antagonist . it interacts with nmda receptor complexes , interrupts cholinergic transmissions , and inhibits the reuptake of noradrenaline and 5-hydroxytryptamine . there is good evidence from experimental animal models , human volunteer studies , and small clinical trials that nmda receptor antagonists relieve some types of neuropathic pain . however , their use is restricted by unpleasant adverse effects , including cardiac ( hypertension and tachycardia , especially of concern in patients with ischemic heart disease ) and neurologic ( e.g. , hallucinations , a sense of disconnection , vivid dreams ) . there is also emerging evidence on the deleterious effect of ketamine on bladder function . the nmda receptor also seems to play a role in the development of opioid tolerance . ketamine in low doses ( e.g. , 1 mg / kg/24 h as a subcutaneous infusion ) has been suggested to reverse or partially reverse opioid tolerance . there has been a general paucity of high - level clinical evidence of efficacy of ketamine in managing cancer - related pain . evidence to support the use of ketamine in chronic cancer pain has mostly been extrapolated from other settings and has been justified primarily from case series and uncontrolled studies . a randomized , controlled trial , although not in cancer pain , also reported the lasting effect of a single ketamine infusion in patients with ischemic pain . on the contrary , a recent , well - powered , randomized , double - blind placebo - controlled study to assess the efficacy and toxicity of ketamine in the management of cancer pain concluded that no net clinical benefit exists for ketamine in this setting . although this is a major finding to refute the role of ketamine in cancer pain management , it is unlikely to influence the current clinical practice unless the results are reproduced in further well - designed , robust studies . therefore , although the evidence base for ketamine as an adjuvant to opioids for cancer pain remains weak , the available literature allows for a cautious conclusion that there is a promise in the potential efficacy of ketamine as an adjuvant to opioids for cancer pain . methadone is a lipophilic and highly protein bound synthetic opioid with a 50%80% oral bioavailability and a half - life of 72 h. methadone has many attractive features as an analgesic , such as the high bioavailability , lack of known metabolic products that produce neurotoxicity , and multiple receptor affinities . not only methadone has activity at the mu - opioid receptor but also it is an inhibitor of serotonin reuptake and a moderate antagonist at the nmda receptor . these properties have raised interest in using methadone for neuropathic pain as well as for opioid tolerance and opioid - induced hyperalgesia . the pharmacoeconomic benefit of methadone has also prompted a reappraisal of this medication since it is much less costly than proprietary sustained - release opioids . however , methadone undergoes n - demethylation through the cytochrome p450 group of enzymes to such a variable extent that there can be interindividual variability in steady - state serum levels . thus , there are multiple potential drug interactions with medications commonly employed in pain management . there is also potential instability in methadone 's effects related to variability in protein binding , excretion , and equianalgesic potency . the most significant risk of parenteral administration of methadone , which is unique to this medication , is qt prolongation , which can lead to potentially fatal arrhythmias including torsades de pointes . close monitoring is especially needed in the presence of other risk factors such as electrolyte abnormality , structural cardiac disease , or some congenital diseases . all of these have led to a divergence between the supporters and critics of methadone utilization . while morphine has long been the  gold standard  by which other opioid analgesics have been compared , methadone has been proposed as a suitable alternative because of its lower potential for opioid - induced neurotoxicity , absence of active metabolites , and nmda - receptor - antagonist activity . unfortunately , this concept has not been widely studied , and a recent systematic review only found two studies comparing methadone to morphine and transdermal fentanyl , which showed comparable efficacy but increased toxicity and dropout rates for methadone . the evidence , however , was considered poor based on the quality of the studies and inconsistent results recent data support the conclusion that s - methadone ( d - isomer ) , by virtue of its nmda - receptor - antagonist activity , affects the development of morphine - induced tolerance and hyperalgesia . using animal models of neuropathic pain , davis and inturrisi examined the ability of s - methadone to attenuate the development of morphine tolerance and to modify nmda - induced hyperalgesia . administration of intrathecal s - methadone reversed tolerance induced by intrathecal morphine . in a related series of experiments , these investigators demonstrated an s - methadone - mediated reduction in hyperalgesia following administration of nmda by d - methadone . these results support the inhibitory effect of s - methadone on the development of morphine tolerance as a result of its nmda - receptor - blocking activity . notwithstanding , there remain limited clinical data relating to methadone 's potential advantage in treating neuropathic pain , hyperalgesia , and tolerance . thus , its potential role in these conditions remains a compelling concept that requires further investigation . methadone may be ideal for those patients with renal impairment as it does not accumulate in renal failure and is insignificantly removed during dialysis . because of its intrinsic extended analgesic effects , methadone may also have an advantage over sustained - release formulations in those with rapid bowel transit times or in those with  short gut syndrome . conducting scientifically sound clinical trials in palliative care patient population is a considerable challenge , reflected by the small number of published trials . the difficulty is due to the fact that the patient population is diverse in age , diagnosis and prognosis , and comorbidities , often with multiple concurrent medications , with unstable , deteriorating clinical states . furthermore , given the heterogeneity of the patient population , pooled response data are often meaningless . therefore , although evidence - based medicine remains a very attractive concept , its practical implication in palliative medicine remains challenging . the paucity of good clinical data for the use of ketamine and methadone in cancer pain management is reflected by this fact . first , this is a young patient with no premorbid medical condition being presented with a diagnosis of a life - limiting illness . the manifestation of this mental anguish can vary widely between individuals , and as described in the case vignette , compounded and impacted on patient 's pain threshold , perception , and coping mechanism . it is interesting to note that every time there was a documented disease progression and treatment failure episode , this was soon followed by an acute pain crisis and more curiously ; every time a new analgesic drug was introduced , there appeared to be a therapeutic response . in the eye of a skeptic , this could partly be explained by an overwhelming desire to continue to search for hope and remedy to the dire situation . second , opioid tolerance and poor absorption due to gastroparesis appeared to play a significant role in the early stages of pain management in this patient . although the clinical evidence of ketamine in alleviating opioid tolerance is not robust , anecdotally , this certainly was deemed useful . the other issue of opioid - induced hyperalgesia is a diagnosis by exclusion , which merits further research . in the present case , an active attempt was made to explain this possibility to the patient with a view to limiting the total number of permissible breakthroughs in any 24-h period . despite the patient being compliant with this strategy , it did not significantly improve the pain management , thereby questioning the validity of this diagnosis . the case also highlights the emotional , professional , and personal challenges palliative care teams face when looking after a young patient who is facing an untimely death at the prime of their life .
assessment and management of complex cancer pain always remains a major challenge for any palliative care team , given its heterogeneity of underlying pathophysiology and limitations of any pharmacotherapy . 
 here , we present a case of complex pain management in a young patient with a life - limiting illness , highlighting the issues of organic and nonorganic contributors of pain and provide some insight into the role of ketamine and methadone as adjunctive therapy to opioid analgesics . a brief literature review is also done to provide the context of use of these adjunctive drugs in this setting .