Larry C. Driver

Patient-Controlled Methylphenidate for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial

PURPOSE To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. RESULTS Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. CONCLUSION Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.

Patient-Controlled Methylphenidate for the Management of Fatigue in Patients With Advanced Cancer: A Preliminary Report

PURPOSE To assess the effects of patient-controlled methylphenidate for cancer-related fatigue. PATIENTS AND METHODS In this prospective open study, 31 patients with advanced cancer and fatigue who scored >/= 4 on a scale of 0 to 10 received methylphenidate 5 mg by mouth every 2 hours as needed for 7 days (maximum, 20 mg/d). Multiple symptoms were assessed daily; the primary end point, fatigue, was measured using the 0 to 10 scale, and the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) was performed at baseline, day 7, and day 28. RESULTS The following mean (+/- standard deviation) scores for 30 assessable patients improved significantly between baseline and day 7: fatigue (0 to 10 scale), 7.2 +/- 1.6 v 3.0 +/- 1.9 (P <.001); overall well-being (0 to 10 scale), 4.5 +/- 2.2 v 2.8 +/- 2.1 (P <.001); fatigue (FACIT-F) subscore, 17.5 +/- 11.3 v 34.7 +/- 10.0 (P <.001); functional well-being, 14.4 +/- 5.9 v 18.3 +/- 6.6 (P <.001); and physical well-being, 13.5 +/- 6.4 v 21.4 +/- 5.0 (P <.001). Anxiety, appetite, pain, nausea, depression, and drowsiness all improved significantly (P <.05). All patients took afternoon or evening doses, and 28 patients (93%) took three or more doses daily. All patients chose to continue taking methylphenidate after 7 days of treatment. No serious side effects were reported. CONCLUSION These preliminary results suggest that patient-controlled methylphenidate administration rapidly improved fatigue and other symptoms. Randomized controlled trials are justified.

Donepezil for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial

PURPOSE To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). PATIENTS AND METHODS Patients with fatigue score >or= 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) for more than 1 week were included. Patients were randomly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days. A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level. All patients were offered open-label donepezil during the second week. FACIT-F and/or the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 11, and 15. The FACIT-F fatigue subscale score on day 8 was considered the primary end point. RESULTS Of 142 patients randomly assigned to treatment, 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis. Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .57) or ESAS (P = .18) between groups. In the open-label phase, fatigue intensity continued to be low as compared with baseline. No significant toxicities were observed. CONCLUSION Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue.

Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine

PurposeChemoneuropathy remains a painful, burdensome complication of cancer treatment for patients receiving a range of chemotherapeutics, yet the cause and persistence of this condition are not fully documented. This study was designed to quantify the longevity of and contributions to neuropathy following treatment with the plant alkaloids paclitaxel and vincristine.MethodsQuantitative sensory testing was conducted approximately 18 months apart on 14 patients, seven of which had been treated with paclitaxel and seven with vincristine and compared to data from 18 healthy control subjects. In addition, skin biopsies were obtained to investigate changes in the density of Meissner’s corpuscles and epidermal nerve fibers (ENFs), the loss of which is thought to contribute to multiple forms of neuropathy.ResultsImpairments in motor skills, as measured by a grooved peg-board, were found. Deficits in touch detection were observed using von Frey monofilaments, as were changes in sharpness detection using a weighted needle device. Using a Peltier device, warmth and heat detection were impaired. These deficits were consistent across time. Remarkably, the average length of time patients reported painful neuropathy was over four and a half years. Skin biopsies were found to be deficient in Meissner’s corpuscles and ENFs.ConclusionsThe combination of widespread deficits in sensory testing and decreases in skin innervation for cancer patients receiving paclitaxel or vincristine document a persistent polyneuropathy which severely impacts these patients. Decreases in Meissner’s corpuscles and ENFs indicate a possible mechanism for the neuropathy.

The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study.

Opioid-induced sedation is a major complication in patients with cancer pain. This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain. Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled. Donepezil 5 mg was given every morning for 7 days. Changes between baseline and Day 7 in sedation, pain, fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale. Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Overall usefulness of donepezil was measured by the patient at the end of the study. In 20 evaluable patients, sedation, fatigue, anxiety, well-being, depression, anorexia and problems with sleep were significantly improved. Side effects included nausea, vomiting, diarrhea, muscle and abdominal cramps, and anorexia. Overall, however, the treatment was well tolerated. Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain. Randomized controlled trials of this agent are justified.

Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients

UNLABELLED Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11 patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissners corpuscles. These results signify a persistent and severe impairment of Aβ, Aδ, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissners corpuscles. PERSPECTIVE The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.

Oral Transmucosal Fentanyl Citrate in the Outpatient Management of Severe Cancer Pain Crises: A Retrospective Case Series

Objective:This retrospective chart review evaluated the efficacy of oral transmucosal fentanyl citrate (OTFC) in an outpatient cancer pain center for patients experiencing severe exacerbations of pain that exceed usual breakthrough pain levels. Patients:Records were reviewed for all patients who received OTFC at M.D. Anderson’s outpatient pain clinic over a three-month time period. OTFC was used in thirty-nine patients experiencing a recent onset of severe pain (≥7 on a 0–10 scale). All patients had cancer, cancer-related pain syndromes, and were opioid tolerant with an oral morphine equivalent daily dosage (MEDD) of ≥40 mg/day. Results:Prior to OTFC treatment, all patients reported a mean pain intensity of 9.0 (SD = 1.2). After OTFC treatment, patients reported a mean intensity of 3.0 (SD = 1.4), a significant reduction in pain intensity (P < 0.001). In most cases, OTFC averted the need for an emergency center visit, parenteral opioids, and hospital admission, which suggests that OTFC may be an effective alternative over intravenous opioids to rapidly titrate analgesia in selected opioid-tolerant cancer patients experiencing severe pain.

Signaling mechanisms mediating muscarinic enhancement of GABAergic synaptic transmission in the spinal cord.

Activation of muscarinic acetylcholine receptors (mAChRs) inhibits spinal nociceptive transmission by potentiation of GABAergic tone through M(2), M(3), and M(4) subtypes. To study the signaling mechanisms involved in this unique mAChR action, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of lamina II neurons were recorded using whole-cell patch clamp techniques in rat spinal cord slices. The mAChR agonist oxotremorine-M caused a profound increase in the frequency of GABAergic sIPSCs, which was abolished in the Ca(2+)-free solution. Inhibition of voltage-gated Ca(2+) channels with Cd(2+) and Ni(2+) largely reduced the effect of oxotremorine-M on sIPSCs. Blocking nonselective cation channels (NSCCs) with SKF96365 or 2-APB also largely attenuated the effect of oxotremorine-M. However, the KCNQ channel blocker XE991 and the adenylyl cyclase inhibitor MDL12330A had no significant effect on oxotremorine-M-induced increases in sIPSCs. Furthermore, the phosphoinositide-3-kinase (PI3K) inhibitor wortmannin or LY294002 significantly reduced the potentiating effect of oxotremorine-M on sIPSCs. In the spinal cord in which the M(3) subtype was specifically knocked down by intrathecal small interfering RNA (siRNA) treatment, SKF96365 and wortmannin still significantly attenuated the effect of oxotremorine-M. In contrast, SKF96365 and wortmannin both failed to alter the effect of oxotremorine-M on sIPSCs when the M(2)/M(4) mAChRs were blocked. Therefore, our study provides new evidence that activation of mAChRs increases synaptic GABA release through Ca(2+) influx and voltage-gated Ca(2+) channels. The PI3K-NSCC signaling cascade is primarily involved in the excitation of GABAergic interneurons by the M(2)/M(4) mAChRs in the spinal dorsal horn.

Acupuncture for Treatment of Uncontrolled Pain in Cancer Patients: A Pragmatic Pilot Study

Purpose. Pain control is an ongoing challenge in the oncology setting. Prior to implementing a large randomized trial at our institution, we investigated the feasibility, safety, and initial efficacy of acupuncture for uncontrolled pain among cancer patients. Hypotheses. Our hypotheses were that the acupuncture treatments provided would be (a) feasible, (b) safe, and (c) a beneficial adjunct to pain management. Study Design. This was a single arm, nonrandomized pragmatic pilot study. Methods. Participants experiencing pain ≥4 on a 0 to 10 numeric rating scale received a maximum of 10 treatments on an individualized basis. Recruitment, attrition, compliance, and adverse events (AEs) were assessed. Pain (Brief Pain Inventory–Short Form), quality of life (MD Anderson Symptom Inventory [MDASI]), and patient satisfaction were assessed at baseline and at the end of treatment. Results. Of 115 patients screened, 52 (45%) were eligible and agreed to participate. Eleven (21%) were lost to follow-up, leaving 41 who completed all study procedures. No AEs were reported. Mean pain severity was 6.0 ± 1.3 at baseline and 3.8 ± 2.0 at follow-up (P < .0001). Pain interference was 6.2 ± 2.3 at baseline and 4.3 ± 2.8 at follow-up (P < .0011). On the MDASI, the mean symptom severity was 4.6 ± 1.8 at baseline and 3.2 ± 1.9 at follow-up (P < .0001), and mean symptom interference was 5.8 ± 2.4 at baseline and 4.1 ± 2.9 at follow-up (P < .002). Prescribed pain medications decreased across the course of the study. Patient satisfaction was high: 87% reported that their expectations were met “very well” or “extremely well”; 90% said they were likely to participate again; 95% said they were likely to recommend acupuncture to others; and 90% reported they found the service to be “useful” or “very useful.” Conclusions. Acupuncture was feasible, safe, and a helpful treatment adjunct for cancer patients experiencing uncontrolled pain in this study. Randomized placebo-controlled trials are needed to confirm these results.

Randomized controlled trial of neurofeedback on chemotherapy-induced peripheral neuropathy: A pilot study

Chemotherapy‐induced peripheral neuropathy (CIPN) is a significant problem for cancer patients, and there are limited treatment options for this often debilitating condition. Neuromodulatory interventions could be a novel modality for patients trying to manage CIPN symptoms; however, they are not yet the standard of care. This study examined whether electroencephalogram (EEG) neurofeedback (NFB) could alleviate CIPN symptoms in survivors.