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This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.

BackgroundMajor depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects.MethodsA double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen’s effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo.ResultsA total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (−23.2; P = .0066 [effect size: 0.9]; −26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (−13.9; P = .0025 [effect size: 1.0]; −15.0; P = .0009 [effect size: 1.1]), SDQ-2 (−4.6; P = .0398 [effect size: 0.7]; −7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (−2.7; P = .0055 [effect size: 1.0]; −2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales.ConclusionsIn patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants.FundingRelmada Therapeutics, Inc.

BackgroundDissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD.MethodsThis retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose).ResultsAmong the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively.ConclusionsThese retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD.FundingRelmada Therapeutics

REL-1017 (esmethadone, d-methadone) is the opioid-inactive d-isomer of racemic d,l-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-d-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical “extinction burst” pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

BackgroundAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality. Hyperlipidemia and vascular subinflammation play critical roles in the pathogenesis of atherosclerosis. Patients with Major Depressive Disorder (MDD) are at higher risk for ASCVD and current antidepressant therapies may carry ASCVD risks. REL-1017 is a novel NMDAR channel blocker which showed rapid, robust, and sustained antidepressant effects, currently in Phase 3 clinical trials for MDD.MethodsWe analyzed total cholesterol (TC), triglycerides (TG), Proprotein Convertase Subtilisin/Kexin 9 (PCSK9), and high-sensitivity C-reactive protein (hs-CRP) from patients enrolled in a Phase-2, multicenter, randomized, double-blind, placebo-controlled, 7-day, 3-arm trial to assess safety, tolerability, pharmacokinetics, and efficacy of REL-1017. Patients were randomized in a 1:1:1 ratio to either placebo, REL-1017 25 mg QD, or REL-1017 50 mg QD. TC, TG, PCSK9, and hs-CRP levels were measured in patients at baseline, day 7 and day 14, 7 days after treatment discontinuation. 6 out of 21 (28% of patients), 6 out of 16 (37%), and 1 out of 19 (5%), were under statin therapy in the placebo, REL-1017 25 and 50 mg groups, respectively.ResultsAt baseline, day 7, day 14 TC levels (mg/dL) were 117.8 ± 30.8, 124.7 ± 34.1, 114.2 ± 18.1; 123.7 ± 59.3, 119.0 ± 28.1, 115.1 ± 14.8; 113.9 ± 22.9, 118.6 ± 29.5, 115.8 ± 25.5 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the subgroup not on statins, TC levels were 127.5 ± 28.6, 134.2 ± 35.0, 117.8 ± 14.8; 131.0 ± 71.7, 121.1 ± 32.9, 118.6 ± 15.4; 115.5 ± 22.1, 121.4 ± 27.1, 119.0 ± 21.9 for placebo (n = 15, 72% of patients), REL-1017 25 mg (n = 10, 63%) and REL-1017 50 mg (n = 18, 95%), respectively. TG were 57.0 ± 25.6, 55.7 ± 20.0, 58.0 ± 34.1; 62.7 ± 52.1, 56.0 ± 31.0, 59.5 ± 32.6; 48.5 ± 25.3, 50.2 ± 18.4, 55.1 ± 21.9 for placebo (n = 21), REL-1017 25 mg (n = 16) and REL-1017 50 mg (n = 19), respectively. Considering the group not on statins, TG were 52.9 ± 27.6, 55.7 ± 23.1, 51.3 ± 26.8; 70.6 ± 63.3, 57.6 ± 38.9, 65.2 ± 38.9; 47.4 ± 25.4, 48.9 ± 17.9, 52.6 ± 19.5 for placebo (n = 15), REL-1017 25 mg (n = 10), and REL-1017 50 mg (n = 18), respectively. Levels of PCSK9, a key player of LDL cholesterol levels, significantly (P ConclusionA 7-day treatment course with REL-1017 did not significantly alter TC, TG, PCSK9, or hs-CRP, suggesting the absence of detrimental effects on ASCVD risk. These data should be confirmed in longer and larger trials.FundingRelmada Therapeutics, Inc.

Purpose/background N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonists are potential agents for the treatment of several central nervous system disorders including major depressive disorder. Racemic methadone, L-methadone, and D-methadone all bind the NMDAR with an affinity similar to that of established NMDAR antagonists, whereas only L-methadone and racemic methadone bind to opioid receptors with high affinity. Therefore, D-methadone is expected to have no clinically significant opioid effects at therapeutic doses mediated by its NMDAR antagonism. Methods We conducted 2 phase 1, double-blind, randomized, placebo-controlled, single- and multiple-ascending-dose studies to investigate the safety and tolerability of oral D-methadone and to characterize its pharmacokinetic profile in healthy opioid-naive volunteers. Results D-Methadone exhibits linear pharmacokinetics with dose proportionality for most single-dose and multiple-dose parameters. Single doses up to 150 mg and daily doses up to 75 mg for 10 days were well tolerated with mostly mild treatment-emergent adverse events and no severe or serious adverse events. Dose-related somnolence and nausea occurred and were mostly present at the higher dose level. There was no evidence of respiratory depression, dissociative and psychotomimetic effects, or withdrawal signs and symptoms upon abrupt discontinuation. An overall dose-response effect was observed, with higher doses resulting in larger QTcF (QT interval corrected using Fridericia formula) changes from baseline, but none of the changes were considered clinically significant by the investigators. Mild, dose-dependent pupillary constriction of brief duration occurred particularly at the 60-mg dose or above in the single-ascending-dose study and at the dose of 75 mg in the multiple-ascending-dose study. No detectable conversion of D-methadone to L-methadone occurred in vivo. Conclusions These results support the safety and continued clinical development of D-methadone as an NMDAR antagonist for the treatment of depression and other central nervous system disorders.

d-Methadone (dextromethadone) is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist that binds to the dizocilpine (MK-801)-binding site of the receptor with an affinity comparable with that of well-established NMDAR antagonists. Considering the similar NMDAR activity of ketamine and d-methadone and the rapid and robust antidepressant effects of ketamine, we compared these 2 drugs in the forced swim test in Sprague-Dawley rats, which has been shown to be predictive of antidepressant activity for drugs with different mechanisms of action including ketamine. This study evaluated the antidepressant-like effect of d-methadone (10, 20, and 40 mg/kg) in the forced swim test 24 hr following a single-dose administration. At all doses, d-methadone significantly (p < .05) decreased immobility of rats compared with vehicle, suggesting antidepressant-like activity. In addition, the effect of d-methadone (20 and 40 mg/kg) on immobility was greater than the effect seen with ketamine (10 mg/kg). Importantly, there were no changes in locomotor activity of rats that could have confounded the immobility effects at all doses (10, 20, and 40 mg/kg) of d-methadone. This is the first demonstration that the NMDAR antagonist, d-methadone, exerts antidepressant-like activity in a preclinical animal model and that its efficacy is similar to or even stronger than that of ketamine, an antidepressant that demonstrates a rapid onset activity and robust efficacy in patients with treatment-resistant depression. d-Methadone is currently being evaluated in a Phase 2a clinical study for patients with treatment-resistant depression and could potentially represent a new effective antidepressant in the growing class of NMDAR antagonists. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

We provide a detailed description of painful neural lesions in hospitalized patients with cancer. A total of 187 consecutive patients with cancer and pain, referred to the pain service of a cancer hospital, were evaluated within 24 hours by two neurologists and followed until discharge or death. Based on history, pain descriptors, physical examination, and radiological and electrophysiological studies, the pain was categorized as neuropathic in 103 patients. The most frequent sites of neurological injury were nerve roots, spinal cord and cauda equina, brachial and lumbosacral plexus, and peripheral nerves. There were no patients with pain caused by injury to the brain. In 93 of these patients, the pain was caused by ongoing neural injury, while, in 10 patients, the neural injury was old and stable. Within these two groups of patients with neuropathic pain, analgesic treatments differed. Prospective studies may determine if categorizing painful neurological injuries in cancer patients based on inferred pathophysiology is useful when deciding among different treatment options.

BACKGROUND The delayed effects (12–16 hours) of transdermal fentanyl make dose titration difficult during acute exacerbations of cancer pain. Patients at the authors' institution routinely are switched from transdermal to intravenous (IV) fentanyl using a 1:1 (transdermal:IV) conversion during severe episodes of pain. METHODS The authors evaluated nine consecutive hospitalized patients with cancer who had severe pain for up to 6 days following the conversion from transdermal to IV fentanyl. Pain intensity was rated using an 11-point (0–10) verbal numeric rating scale (NRS). All 9 patients initially reported their pain intensity with movement as ≥ 8 during treatment with transdermal fentanyl. Eight patients initially reported their pain at rest as ≥ 8. In each patient, all transdermal patches were removed, and a continuous infusion (CI) delivering IV fentanyl at the same hourly rate was initiated simultaneously. Demand boluses of IV fentanyl equivalent in dosage to 50–100% of the CI rate remained available by patient-controlled analgesia (PCA). Pain intensity (0–10), sedation (0–3), and hourly fentanyl requirements (micrograms per hour) were assessed and recorded immediately prior to patch removal and at least once daily after the initiation of IV fentanyl. The CI and demand boluses were titrated whenever necessary on the basis of pain intensity and supplemental PCA use. RESULTS All 9 patients reported mild levels (≤ 4) of pain at rest within 5 days. The median time to achieve mild levels of pain at rest was 1.5 days. Six patients achieved mild levels of pain with movement within 3 days. Three patients never achieved mild levels of pain with movement while receiving IV fentanyl. No serious side effects were reported. CONCLUSIONS The conversion from transdermal to IV fentanyl can be accomplished safely and effectively using a 1:1 (transdermal:IV) conversion during acute exacerbations of cancer pain. Cancer 2003;97:3121–4. © 2003 American Cancer Society. DOI 10.1002/cncr.11457

Background Some patients with advanced dementia cannot convey the experience of pain verbally and may react to pain with aggressive and agitated behaviors. We hypothesized that unrecognized pain could contribute to agitation and that low dose opioid therapy might reduce agitation by reducing pain. We therefore attempted to determine the effect of opioids on agitation in demented patients. Methods We administered placebo for 4 weeks and a long-acting opioid for another 4 weeks to nursing home patients with advanced dementia and severe agitation despite treatment with psychotropic drugs. Patients and study nurses did not know if the medication administered was placebo or opioid. We measured the Cohen-Mansfield Agitation Inventory (CMAI) score at baseline and every two weeks. Results Among 47 patients who entered the study, 25 completed the two phases. The median age for the 25 patients was 85.5 years. Analyses of the data of these 25 patients and of the patients

The successful use of methadone in cancer pain has been supported by numerous case reports and clinical studies. Methadone is usually used as a second or third line opioid medication. As the use of methadone increases we are facing the challenge of converting methadone to other opioids as part of sequential opioid trials. Data on the equianalgesic ratios for the substitution of other opioids for methadone are lacking. We present prospective data on 13 consecutive rotations from methadone to a different opioid. The opioid rotation was followed by escalation of pain and/or severe dysphoria, not controlled by a rapid increase in the dose of the second opioid, in 12 of the 13 patients. Only one patient was successfully maintained on the second opioid after the discontinuation of methadone, while 12 patients required a switch back to methadone. We conclude that opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria. These symptoms may not improve despite upward titration of the second opioid. A uniformly accepted conversion ratio for substituting methadone with another opioid is currently not available. More data on the rotation from methadone to other opioids are needed.

To provide a detailed description of the recommendations of a Palliative Care Service (PCS) and to describe the impact of these recommendations on the care of terminally ill patients in an academic medical center, we describe data from all consecutive patients referred by their attending physicians to the PCS of an academic teaching hospital over a 15-month period. All patients were seen within 24 hours of consultation request. Data were collected prospectively on the day of discharge or death. Attention was focused on six recommendations and their implementation: 1) discussion about prognosis and goals of care; 2) pursuing documentation of advance directives; 3) discussion about foregoing specific treatments and/or diagnostic interventions; 4) family and patient support; 5) discharge planning; and 6) symptom management. Over a 15-month period, we collected data on 325 patients. The most frequent diagnoses were cancer, dementia, and HIV disease. The patients were followed for a mean of 7.6 days. The average number of recommendations was 4.2 per patient and 91% of the recommendations were implemented (3.8 per patient). Recommendations increased to 5.3 per patient and the implementation rate increased to 97% (5.1 per patient) for the 44 patients transferred to the Palliative Care Unit (PCU). PCS consultations result in multiple recommendations with a very high implementation rate. The number of recommendations and the high implementation rate suggest a strong need for palliative care services within acute care hospitals.

BACKGROUND. All major cancer centers in the United States are equipped with pain management consultation services. We report on the outcome of such consultations within 24 hours from the intervention. METHODS. All consecutive patients referred to the pain management service of a tertiary care cancer center were assessed before and 14-24 hours after the intervention. RESULTS. A total of 45 patients completed the study. The mean current pain intensity score was 5.2 on the Visual Analogue Scale before the consultation and 2.7 7 after the consultation (P < 0.05). The pain was described as excruciating on the Categorical Scale by three patients before the consultation and by no patients after the consultation. CONCLUSIONS. In hospitalized cancer patients with difficult to control pain, cancer pain consultations result in a measurable effect within 24 hours of the pharmacologic intervention. To avoid unnecessary suffering, timeliness is of the utmost importance when requesting and delivering cancer pain consultations.

The safety and efficacy of intraspinal opioids as therapy for selected patients with cancer pain are well-established. The choice of the appropriate drug is influenced by many variables that are to date incompletely elucidated. The cost of therapy is an increasingly important component of decision-making. This report describes the management of a patient who achieved excellent pain control with the administration of epidural sufentanil and bupivacaine. Daily Average Wholesale Price for sufentanil was, however, $698. Until the data comparing the efficacy of different epidurally administered opioids in the treatment of cancer pain are available, we suggest that treatment with more costly opioids be reserved for patients for whom analgesia cannot be achieved after maximizing epidural morphine analgesia with aggressive side-effect management.

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget's disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were -1.39 (SE=0.43) for placebo, and -1.53 (0.71), -1.26 (0.81), -1.42 (0.65), and -4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P=0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.

Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.

High doses of parenteral opioids can cause multifocal myoclonus and seizures. Spasticity has been reported in patients receiving intraspinal opioids. In this article, we describe a patient who developed reversible spastic paraparesis with prominent extensor spasms in the legs while receiving an infusion of intravenous methadone at 100 mg/hr. We discuss clinical presentation and possible pathophysiologic mechanisms of opioid side effects on the somatic motor system.

The use of sumatriptan for the treatment of migraine and cluster headache is well established. Sumatriptan has also been reported to be effective for the treatment of postdural puncture headache, postictal headache, and headache related to intravenous immunoglobulin infusion. We report two patients with headache caused by locally invasive head and neck cancer relieved by oral sumatriptan.

Although standards for palliative treatment of cancer patients at end of life are available, their use is perceived to vary among institutions depending on the prevailing philosophy of care. In this retrospective study, we reviewed the treatment of dying cancer patients receiving intravenous morphine transferred from a cancer center to a palliative care hospital. We recorded the dose of morphine and the use of other palliative medications, including adjuvant analgesic drugs. Although morphine doses tended to decrease after the transfer, the use of palliative medications was similar in the two institutions.

The prevalence of pain caused by injury to the central nervous system (CNS), or central pain (CP), in cancer patients is unknown. In order to define prevalence and characteristics of central pain in hospitalized patients with cancer, we performed a retrospective review of medical records of patients evaluated by 2 different services: the Pain Service and the Neurology Service, at Memorial Sloan-Kettering Cancer Center. The prevalence of CP in these patients was 4% and 2%, respectively. Primary and metastatic tumors and their therapy, including surgery, radiation and chemotherapy, were all potential causes of CP. The occurrence of CP in patients with primary CNS tumors was higher in patients with spinal cord tumors compared to patients with brain tumors (P < .0001). © 2003 by the American Pain Society

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

We provide a detailed description of painful neural lesions in hospitalized patients with cancer. A total of 187 consecutive patients with cancer and pain, referred to the pain service of a cancer hospital, were evaluated within 24 hours by two neurologists and followed until discharge or death. Based on history, pain descriptors, physical examination, and radiological and electrophysiological studies, the pain was categorized as neuropathic in 103 patients. The most frequent sites of neurological injury were nerve roots, spinal cord and cauda equina, brachial and lumbosacral plexus, and peripheral nerves. There were no patients with pain caused by injury to the brain. In 93 of these patients, the pain was caused by ongoing neural injury, while, in 10 patients, the neural injury was old and stable. Within these two groups of patients with neuropathic pain, analgesic treatments differed. Prospective studies may determine if categorizing painful neurological injuries in cancer patients based on inferred pathophysiology is useful when deciding among different treatment options.

The purpose of this study was to assess the reliability and validity of facial expressions as pain indicators in patients with severe dementia. Based on interviews with patients who could report pain, we defined characteristics of decubitus ulcers associated with reports of pain during dressing changes. We then evaluated 9 patients who had ulcers with these characteristics but were unable to communicate verbally because of severe dementia. We videotaped their facial expressions before and during their decubitus ulcer dressing change. We showed the videotape segments, in random order, to 8 medical students and 10 nurses. The 18 viewers were asked to infer the presence or absence of pain based on their observations of the patients' facial expressions and vocalizations. The dressing change of decubitus ulcers extending beyond the subcutaneous tissue, covering an area of at least 9 cm(2), and with a moist surface, was always reported as painful by study patients able to report (95% confidence interval of 69-100%). The intraclass correlation coefficient for the answers of the 18 viewers evaluating each videotape segment for the presence of pain was 0.64. Sensitivity, specificity, and positive and negative predictive values of viewers' ratings of facial expressions and vocalizations as a measure of the presence of pain were: 0.70, 0.83, 0.90, and 0.81. The intraclass correlation coefficient for the answers rating pain intensity was only 0.10, indicating only slight agreement beyond chance. Assuming dressing changes of ulcers reported as painful by communicative patients are also painful in non-verbal severely demented patients, clinician observations of facial expressions and vocalizations are accurate means for assessing the presence of pain, but not its intensity, in patients unable to communicate verbally because of advanced dementia.

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) current (I(HERG)) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I(HERG), with IC(50) values in the 1 to 10 microM range. The other drugs tested were far less potent with respect to I(HERG) inhibition. Compared with the reported maximal plasma concentration (C(max)) after administration of therapeutic doses of these drugs, the ratio of IC(50)/C(max) was highest for codeine and morphine (455 and400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I(HERG). In contrast, the lowest ratios of IC(50)/C(max) were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I(HERG) was rapid, with steady-state inhibition achieved within 1 s when applied at its IC(50) concentration (10 microM) for I(HERG) block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although approximately 10% of the available HERG K(+) channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I(HERG) in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.

Objective To characterize the symptom experience of a cohort of intensive care unit (ICU) patients at high risk for hospital death. Design Prospective analysis of patients with a present or past diagnosis of cancer who were consecutively admitted to a medical ICU during an 8-month period. Setting Academic, university-affiliated, tertiary-care, urban medical center. Patients One hundred cancer patients treated in a medical ICU. Intervention Assessment of symptoms. Measurements Patients’ self-reports of symptoms using the Edmonton Symptom Assessment Scale (ESAS), and ratings of pain or discomfort associated with ICU diagnostic/therapeutic procedures and of stress associated with conditions in the ICU. Main Results Hospital mortality for the group was 56%. Fifty patients had the capacity to respond to the ESAS, among whom 100% provided symptom reports. Between 55% and 75% of ESAS responders reported experiencing pain, discomfort, anxiety, sleep disturbance, or unsatisfied hunger or thirst that they rated as moderate or severe, whereas depression and dyspnea at these levels were reported by approximately 40% and 33% of responders, respectively. Significant pain, discomfort, or both were associated with common ICU procedures, but most procedure-related symptoms were controlled adequately for a majority of patients. Inability to communicate, sleep disruption, and limitations on visiting were particularly stressful among ICU conditions studied. Conclusions Among critically ill cancer patients, multiple distressing symptoms were common in the ICU, often at significant levels of severity. Symptom assessment may suggest more effective strategies for symptom control and may direct decisions about appropriate use of ICU therapies.

Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy.

Methadone is a very effective second-line opioid for treatment of cancer pain. However, the starting doses of methadone indicated on opioid conversion charts may over-estimate the dose of intravenous (i.v.) methadone needed. In this report, we describe four patients with cancer-related pain treated with continuous i.v. morphine and hydromorphone. Because of persistent pain and opioid side effects limiting increases in opioid dose, each patient was switched to i.v. methadone. All four patients had excellent pain relief without significant side effects at a dose that, according to the available conversion charts, was approximately 3% of the calculated equianalgesic dose of hydromorphone. When converting from continuous i.v. hydromorphone to continuous i.v. methadone, much lower doses than those suggested by the opioid conversion charts should be used as starting doses.