Role of Ketamine and Methadone as Adjunctive Therapy in Complex Pain Management: A Case Report and Literature Review

INTRODUCTION

Pain management remains one of the major challenges in the practice of palliative medicine. 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.[1] 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.

CASE REPORT

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. Histology revealed poorly differentiated adenocarcinoma of the colon with lymphovascular and perineural invasion. 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 pain became an issue for the first time at this point. The patient reported gradual onset, constant, dull pain in the right inguinal and thigh area. It did not have any neuropathic feature to it. 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 naïve 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, at least three different reasons for the suboptimal pain control were identified. 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^th 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 was also tried with minimal benefit and, therefore, ceased after 5 days. 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. Pastoral care visits were declined.

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. The patient passed away peacefully in hospital 11 months after his original diagnosis.

DISCUSSION

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.

The patient presented here highlights the complexity of pain management at several different levels. First, this is a young patient with no premorbid medical condition being presented with a diagnosis of a life-limiting illness. This alone is sufficient to cause severe anxiety, psychospiritual and existential distress. 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.