Eric Prommer

Oxymorphone: a review

Oxymorphone (oxymorphone hydrochloride) (14-hydroxy-dihydromorphinone), a semisynthetic μ-opioid agonist, was first approved by the US Food and Drug Administration in 1959. Oxymorphone is considered a more potent opioid than its parent compound, morphine. Recently, an immediate-release and long-acting oral formulation of this drug was developed that makes oxymorphone a new option in treating moderate to severe pain. This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this new option in treating moderate to severe pain.

Ketamine for Pain: An Update of Uses in Palliative Care

Ketamine is a lipophilic, general anesthetic. When given at subanesthetic doses, it also has been found to be an effective analgesic, with efficacy in cancer-associated neuropathic pain, ischemic pain, and regional pain syndromes. It can be administered orally, intravenously, subcutaneously, and topically, and interacts with several receptors important in pain management, most importantly the N-methyl-D aspartate (NMDA) receptor. Blockade of the NMDA receptor is associated with reversal of opioid tolerance. Ketamine is metabolized via cytochrome P450 3A4, although no significant interactions have been reported. Ketamine is considered one of the World Health Organization (WHO) essential drugs for the management of refractory pain.

Methylphenidate Established and Expanding Roles in Symptom Management

Methylphenidate is a psychostimulant originally used for the treatment of attention-deficit disorder. Methylphenidate inhibits neuronal neurotransmitter transporters involved in the uptake of dopamine and norepinephrine at the level of the synapse. Inhibition of these transmitter transporters leads to increased concentrations of dopamine and norepinephrine in the synapse, which results in increasing alertness. The stimulant effect of methylphenidate has been used for the treatment of major depression, poststroke depression, cognitive enhancement in patients with brain tumors, neurodegenerative disorders, HIV disease, fatigue, and as a treatment for delirium and sedation associated with opioid use. Other areas where methylphenidate has been evaluated include gait disorders in the elderly individuals and the treatment of apathy in dementia. Analgesic effects have been demonstrated in preclinical models but true analgesic effects remain to be proven in humans. This article reviews the current use of methylphenidate for symptom management with a critical look at the evidence base for its efficacy in the conditions described.

The Role of Fentanyl in Cancer-Related Pain

Fentanyl is a lipophilic, short-acting, synthetic opioid with a piperidine chemical structure. Fentanyl is an effective analgesic for cancer pain, and newer formulations such as the transmucosal and buccal forms have shown efficacy for the management of cancer-related breakthrough pain. This article reviews the pharmacodynamics, pharmacology, and clinical efficacy for this new option in treating moderate to severe pain.

Management of Pain in the Elderly at the End of Life

Pain is one of the symptoms most frequently encountered in elderly patients at the end of life. The management of pain in the elderly in general has been associated with undertreatment. The geriatric population has been identified as a challenging population with respect to pain management because of issues related to co-morbidities, polypharmacy and cognitive dysfunction. In the geriatric population, the assessment of pain requires measurement of pain intensity, delineation of opioid responsiveness, and clarification of the impact of pain on patients’ psychological, social, spiritual and existential domains. Effective pain management is guided by the World Health Organization (WHO) analgesic stepladder, which categorizes pain intensity according to severity and recommends analgesic agents based on their strength and works effectively in the elderly patient population. Step 1 is reserved for mild pain. Patients in this category are treated with nonopioid analgesics such as acetaminophen, or a nonsteroidal anti-inflammatory, with consideration of an adjuvant analgesic if necessary. Step 2 is reserved for patients experiencing mild to moderate pain who are already taking a nonopioid analgesic, with or without an adjuvant analgesic, but are still experiencing poor analgesic control. Step 2 agents include acetaminophen products containing hydrocodone, oxycodone, codeine and tramadol. Patients with moderate to severe pain require strong analgesics belonging to step 3 of the WHO analgesic stepladder. Step 3 opioids include morphine, hydromorphone, fentanyl, levorphanol, methadone and oxycodone. Familiarity with opioid pharmacokinetics, equi-analgesic dosing and adverse effects is necessary for the safe and effective use of these drugs. The appropriate use of adjuvant analgesics such as antiepileptic drugs, antidepressants and local anaesthetics can enhance the use of opioids, especially in cases where opioid responsiveness may be in question, such as with neuropathic pain. This paper will provide an overview of the analgesic considerations for elderly patients at the end of life.

Adverse Effects in Hospice Patients with Chronic Kidney Disease Receiving Hydromorphone

BACKGROUND Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency. METHODS In this study we sought to determine the prevalence of neuroexcitation in patients with renal insufficiency who were given hydromorphone, as measured by the glomerular filtration rate (GFR), and to investigate factors associated with increased risk of neuroexcitation in this patient group. For the 12- month period from June 2007 through June 2008, charts of inpatient hospice patients that showed a glomerular filtration rate of <60 (mL/min/1.73 m(2)) and hydromorphone administration for pain control via continuous infusion were reviewed for the occurrence of neuroexcitatory effects, including tremor, myoclonus, agitation, cognitive dysfunction, and seizures. RESULTS Overall prevalence of neuroexcitatory effects were: tremor 11 (20%), myoclonus 11 (20%), agitation 26 (48%), and cognitive dysfunction 21 (39%). No seizures were observed. No neuroexcitatory effects were observed for the lowest quartile of dose or duration of hydromorphone. There was a strong and graded increase in neuroexcitatory effects with increasing quartile of dose or duration of hydromorphone for agitation (dose, p<0.0001; duration, p<0.0001) and cognitive dysfunction (dose, p<0.0002; duration, p<0.002). Consistent but weaker trends were observed for tremor and myoclonus. CONCLUSION Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest.

Intranasal fentanyl for pain control: current status with a focus on patient considerations

Of several newer delivery systems under development and investigation for the administration of opioids, the intranasal route has received a substantial amount of attention. Intranasal administration is a convenient form of delivery that is applicable to several opioids. It has the potential for self-administration, combined with a rapid onset of action, allowing for patient-controlled analgesia. In clinical practice, intranasal administration has been found to be a reliable drug delivery method that is familiar to patients. Intranasal opioids have proven to be useful in both in-hospital and out-of-hospital pain management settings. Fentanyl, a highly lipophilic step 3 opioid, has been evaluated for intranasal administration. The purpose of this review is to examine the role of the nasal route of opioid administration and examine the evidence base for the use of fentanyl intranasally.

Established and potential therapeutic applications of octreotide in palliative care

Octreotide acetate was developed as a pharmacologically stable, long-acting analogue of the hormone somatostatin. Mimicking the actions of somatostatin, octreotide has been used for its antisecretory effects. Randomized control trials have established the efficacy of octreotide for malignant bowel obstruction and for chemotherapy-induced diarrhea. Octreotide has proven to be an effective agent for symptoms of carcinoid syndrome. Newer uses include for bone marrow transplantation, infectious diarrheal syndromes, and management of hepatic metastases. More evidence is needed for the establishment of its efficacy for hypercalcemia, pain, pleural effusions, diarrhea after celiac plexus block, and malignant ascites.

Palliative Oncologists: Specialists in the Science and Art of Patient Care

DOI: 10.1200/JCO.2014.60.3274 Case Vignette “We’ve been waiting for you to come on the oncology service,” the oncology fellow said, as the resident and nurse practitioner on service looked on. “We have a really challenging case.” Our patient was a frail 77-year-old woman with unresectable pancreatic adenocarcinoma, saddle pulmonary embolus, protein calorie malnutrition, hepatitis C, and recurrent infections, all of which had resulted in a lengthy hospital stay. Her cancer had progressed despite two lines of chemotherapy. She wanted more treatment, but had been told she was too weak. In our first meeting, she told me that her goal was “to get strong enough for more chemotherapy.” She had interpreted the previous oncology attending’s statement about her fitness for chemotherapy as a challenge, and thought, “If I can get stronger, I can get more.” Knowing and trusting my colleague, I imagine his statement was meant as a stepping stone toward a transition to hospice. Her family fiercely defended her desire for rehabilitation as well (“Don’t take away her hope,” they had said), so she remained in a hospital-based limbo, too weak for physical therapy and without sufficient understanding of her prognosis to allow a seamless transition to hospice. As a dual board–certified medical oncologist and palliative care physician, I respected her hopefulness and recognized the challenges that I faced as a result of the complex and nuanced conversations that had occurred before I became involved in her care. I also recognized her profound suffering and that of her family, both because of my conversations with them and because of the heaviness I felt in my heart when entering her room. I suspect that every oncologist knows a version of the above scenario, and knows that heaviness of heart, too. As physicians, we are often most comfortable in the medical and fact-based realms. However, in my palliative care training, I was taught to listen to the so-called limbic music in a room to try to identify the causes of suffering. Often the solution in a difficult clinical encounter lies in addressing emotional and spiritual needs as well as physical ones. Our team aggressively managed the patient’s pain and nausea and then explored her suffering. As a member of a three-generation ranching family, she had been physically active until her diagnosis, and felt betrayed by her body. In the hospital, without her daily dose of open sky, she felt trapped. She did not have a will and worried about who would run the ranch after she passed. Her sons had a contentious relationship and often disagreed about how to care for her. She was overwhelmed and, frankly, not ready to die. She suffered in many realms—physical, emotional, interpersonal, financial and existential— and her suffering affected her decision making. By identifying and addressing the causes of her suffering in the context of our goals-of-care discussions, we helped her to understand that she was not going to regain the physical ability to run the ranch, but that she might be able to see it again, that we could begin to address some of her financial and relationship concerns, and that those things were possible without more chemotherapy. Before her death in the hospital, she had completed a medical power of attorney, had met with her sons and a family lawyer to make a will, and had the opportunity to grieve openly with her sons about her anticipated death. From an educational perspective, an oncology fellow, resident, and nurse practitioner learned to recognize and assess “total pain,” Dame Cicely Saunder’s concept of suffering that encompasses physical, psychological, social, and spiritual domains. This vignette illustrates how palliative oncology experts can influence patient care and education in meaningful ways, and also how palliative care training adds a different dimension to the core skills that all oncologists use.

Role of Haloperidol in Palliative Medicine An Update

Haloperidol is a butyrophenone neuroleptic agent characterized as a high-affinity dopamine antagonist, originally used for the treatment of schizophrenia. Awareness of the role dopamine plays in many symptoms in palliative care, such as nausea, vomiting, and delirium, has led to the use of dopamine antagonists such as haloperidol for the treatment of these symptoms in the palliative care setting. Listed as 1 of the 25 important drugs in palliative care, haloperidol can be administered by multiple routes and can be given without dose alteration in the setting of both renal and hepatic insufficiency. Haloperidol is extensively metabolized in the liver, with CYP3A4 the chief cytochrome oxidase responsible for metabolism. This article will review the pharmacology, pharmacokinetics, and current uses of haloperidol in palliative medicine. There will be an examination of the evidence base for the use of haloperidol in palliative medicine.