Neil A. Hagen

Breakthrough pain : definition, prevalence and characteristics

&NA; In the cancer population, the term breakthrough pain typically refers to a transitory flare of pain in the setting of chronic pain managed with opioid drugs. The prevalence and characteristics of this phenomenon have not been defined, and its impact on patient care is unknown. We developed operational definitions for breakthrough pain and its major characteristics, and applied these in a prospective survey of patients with cancer pain. Data were collected during a 3 month period from consecutive patients who reported moderate pain or less for more than 12 h daily and stable opioid dosing for a minimum of 2 consecutive days. Of 63 patients surveyed, 41 (64%) reported breakthrough pain, transient flares of severe or excruciating pain. Fifty‐one different pains were described (median 4 pains/day; range 1–3600). Pain characteristics were extremely varied. Twenty‐two (43%) pains were paroxysmal in onset; the remainder were more gradual. The duration varied from seconds to hours (median/range: 30 min/1–240 min), and 21 (41%) were both paroxysmal and brief (lancinating pain). Fifteen (29%) of the pains were related to the fixed opioid dose, occurring solely at the end of the dosing interval. Twenty‐eight (55%) of the pains were precipitated; of these, 22 were caused by an action of the patient (incident pain), and 6 were associated with a non‐volitional precipitant, such as flatulence. The pathophysiology of the pain was believed to be somatic in 17 (33%), visceral in 10 (20%), neuropathic in 14 (27%), and mixed in 10 (20%). Pain was related to the tumor in 42 (82%), the effects of therapy in 7 (14%), and neither in 2 (4%). Diverse interventions were employed to manage these pains, with variable efficacy. These data clarify the spectrum of breakthrough pains and indicate their importance in cancer pain management.

Cooperative hernia study. Pain in the postrepair patient.

BACKGROUND The Cooperative Hernia Study assessed postoperative pain in a prospective trial as part of a larger study looking at the recurrence rate and other morbidity of the Bassini, McVay, and Shouldice repairs. METHODS Patients were randomized to one of three surgical hernia repairs. Patients were seen in follow-up at 6, 12, and 24 months and were assessed for the presence of pain, numbness, paresthesia, and recurrence. RESULTS Three hundred fifteen patients were seen in follow-up, with 276 seen at the 2-year mark. At 1 year, 62.9% of patients had groin or inguinal pain and 11.9% of patients had moderate to severe pain; 53.6% had pain and 10.6% of patients continued to report moderate to severe pain 2 years postoperatively. The predictors for long-term postoperative pain were as follows: absence of a visible bulge before the operation (p < 0.001); presence of numbness in the surgical area postoperatively (p < 0.05); and patient requirement of more than 4 weeks out of work postoperatively (p < 0.004). Three distinct chronic pains were identified. The most common and most severe pain was somatic, localized to the common ligamentous insertion to the public tubercle. The second was neuropathic and was referable to the ilioinguinal or genitofemoral nerve distribution. This was likely because of injury to the genitofemoral nerves, either at surgery or subsequently by encroachment of scar. The third pain was visceral, ejaculatory pain. Twenty-four percent of patients had postoperative numbness at 2 years, independent of the type of repair. Numbness was most common in the distribution of cutaneous branches of the ilioinguinal and iliohypogastric nerves. CONCLUSION Pain or numbness are common late sequelae of traditional external surgical hernia repairs. Strategies need to be developed to reduce the risk of these complications.

Chronic nausea and morphine-6-glucuronide.

Morphine-6-glucuronide is an active metabolite of morphine that has analgesic properties and is measurable in the plasma and cerebrospinal fluid of patients treated with this opioid. Decreased clearance of the compound has been observed in patients with renal insufficiency, and this has been associated with an increase in the ratio of morphine-6-glucuronide to morphine. Clinical effects from accumulation of morphine-6-glucuronide have not been described with the exception of case reports in which patients with renal failure were noted to develop opioid toxicity with high plasma levels of the metabolite and low levels of the parent drug. We describe a patient who experienced chronic nausea and an episode of confusion while treated with a small, stable dose of oral morphine in the setting of mild renal insufficiency. Relatively high levels of morphine-6-glucuronide were measured and all symptoms resolved promptly as the concentration of this metabolite declined. This case provides suggestive evidence that morphine-6-glucuronide can produce clinically significant effects in patients with mild renal insufficiency.

Alternative therapy use in neurologic diseases: Use in brain tumor patients

Background: The extent of alternative therapy use in brain tumor patients is unknown, but it may be frequent and seems important to those who use it. Objective: To characterize alternative therapy use in brain tumor patients. Methods: Prospective questionnaire-based survey of 167 brain tumor patients who attended a cancer center in Southern Alberta. Physicians completed forms describing clinical information such as disease status. Results: The response rate was 91% (167/184). Twenty-four percent of patients used alternative therapies and often more than one therapy at the same time. Motivation to use these therapies was influenced by the desire for patient-focused treatment and a perceived need to take charge. Alternative therapy users were younger (p = 0.04) and more likely to be on sick or disability leave (p = 0.02), to come in for repeat visits (p = 0.05), and to have received conventional treatments (p = 0.01). Users tended to have lower quality of life with respect to physical well-being, functional well-being, and a specific brain tumor subscale. Clinical variables, such as disease status, tumor type, and Karnofsky Performance Score, were not related to alternative therapy use. Major changes in number and types of alternative therapy use occurred during the study period. No major side effects or tumor responses were seen with alternative therapies. Conclusions: Alternative therapy use in brain tumor patients is common and may reflect unmet patient needs with respect to their cancer care within the current model of health care delivery.

Patterns of Pain and Interference in Patients with Painful Bone Metastases: A Brief Pain Inventory Validation Study

Bone metastases are prevalent, painful, and carry a poorer prognosis for pain control compared with other cancer pain syndromes. Standard tools to measure pain have not been validated in this patient population, and particular subgroups with more challenging symptoms have yet to be identified and studied. The objectives of this study were 1) to validate the psychometric properties of the Brief Pain Inventory (BPI) and its Pain and Interference subscales in patients with clinically significant metastatic bone pain requiring palliative radiotherapy and 2) to examine differences in BPI subscales among predefined subgroups of bone metastases patients. A total of 258 patients evaluated and treated through a rapid access radiation therapy clinic between July 2002, and November 2006, were included in the analysis. High internal consistency of the BPI subscales of Pain, Activity interference, and Affect interference was demonstrated by Cronbachs alpha between 0.81 and 0.89. Removing sleep interference improved model fit in confirmatory factor analysis. The BPI revealed an alarming pattern in patients with lower body metastases, who reported substantial interference of activity even though pain levels were mild or moderate. Such patients may require prompt clinical attention to better meet their needs. Finally, the allocation of interference from sleep within the BPI framework, in our population of pain patients, requires further study.

A formal feasibility study of sublingual methadone for breakthrough cancer pain

We conducted a feasibility study of sublingual methadone for breakthrough cancer pain, to determine whether a larger, randomized trial was warranted, and to identify a study design that would be likely to succeed. From approximately 1930 patients in the initial pool, nine patients were enrolled. Five patients completed the study, generating data on 83 discrete episodes of breakthrough cancer pain at optimal dose. Mean pain intensity dropped by 1.7 points (on a 10 point numerical scale) within 10 min of sublingual methadone administration, and by 3.2 points after 15 min. No serious or severe toxicity was encountered. Based on the results of this feasibility study, a larger randomized clinical trial of sublingual methadone for breakthrough cancer pain using this trial model would not be successful. Extensive information obtained from small numbers of carefully studied patients provides proof of concept that sublingual methadone is effective, safe, and well tolerated.

Do changes in brain sodium channels cause central pain

An estimated 200,000 Americans have “central pain”—chronic pain associated with lesions of the brain or spinal cord. Central pain often accompanies lesions that include any portion of the spinothalamocortical pain pathways mediating pain and temperature1 and has been refractory to treatment. A single randomized trial suggesting that amitriptyline reduces poststroke pain2 appeared more than a decade ago. Two recent clinical trials in central pain expand the therapeutic options. A placebo-controlled crossover study of lamotrigine in 31 patients with poststroke pain showed a modest but significant reduction in pain,3 and, in this issue of Neurology, Attal et al.4 report that in 10 patients with spinal cord injury and 6 patients with poststroke pain, acute infusion of lidocaine transiently reduced spontaneous pain, pain evoked by light touch, and tingling. Attal et al. point out that lidocaine’s well-known effect of reducing ectopic discharge mediated by voltage-gated sodium channels in injured peripheral afferents …

Tetrodotoxin for Moderate to Severe Cancer-Related Pain: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Trial

Objective This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain. Methods Eligible patients were randomized to receive TTX (30 μg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures. Results 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis “intent-to-treat” population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p = 0.0460). The p value was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient. Conclusions Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114).

Design and Implementation of an Online Course on Research Methods in Palliative Care: Lessons Learned

BACKGROUND Research capacity in palliative and end-of-life care is less than some other fields of medicine where there is a longer track record of biomedical research. Palliative medicine clinicians often receive little or no formal research training during their postgraduate education; hence, education efforts may prove pivotal to increasing palliative care research capacity. To that end, our group established a national online training program on palliative care research methodologies, called Foundations of Palliative Care Research. This report describes the development and implementation of the course, and its evaluation. To inform decisions on the overall course objectives, length, design, and implementation, formal needs assessments were conducted through surveys of Canadian palliative medicine residency program directors and of Canadian palliative medicine residents. METHODS A 12-week, online, module-based course was designed. The first iteration of the course was offered to English-speaking palliative medicine residents from across Canada between October 2008 and March 2009. The course utilized Web-based communication methods, and was delivered using a combination of asynchronous and synchronous learning strategies and activities. RESULTS Ten palliative care residents from different parts of the country registered and all completed the course with passing marks. Participants evaluated the course through a post course survey. The formal evaluation of the course, along with successes, challenges, and lessons applicable to future ventures, are discussed.

DHE‐45 for acute migraine

decline is consistent with “the reported neuropathologic changes of Alzheimer’s disease in aging DS patients: and with more recent postmortem brain studies in DS.4” We believe that this assertion is unjustified, for the following reasons. Solitare and Lamarche2 pointed out that their data were limited because of the paucity of numbers and of inclusion of men as well as women in their study. Furthermore, absent were clinical histories and neuropathologic dwriptions of their material. Finally, there was no control material. An extensive study by Dekaban and Sadowsky5 indicates, in both men and women, that normal brain weight falls by about 1.6% per decade during adulthood. a rate of decline not significantly different from that calculated from the Solitare and Lamarche* data (see above). Our report1 is consistent with the absence of accelerated agerelated atrophy in healthy DS subjects. The DS subjects we describedl were healthy and, except for 1 of the 7 older subjects, not demented. Our findings were as follows: (1) Quantitative CT demonstrated a statistically significant (p < 0.05) increase in lateral ventricle volume in relation to age in the DS subjects, by 2.0% per decade, indicative of progressive loss of neuronal mass. (2) Our age-matched controls also showed significant dilatation of the lateral ventricles by 2.15% per decade. (3) The mean rates of dilatation per decade did not differ significantly (p > 0.05) between the DS subjects and controls. Thus, in these cross-sectional studies, there was no greater rate of lateral ventricular dilatation in nondemented DS subjects as compared with controls. A pathologic process in addition to normal aging need not be postulated for these DS subjects, as suggested by Pearlson and Warren. In a recently published abstract,6 we went on to examine rates of change in brain maas and ventricular volume in demented as compared with nondemented older DS Subjects, using quantitative CT in a longitudinal analysis lasting up to 2 years. Luxenberg et al7 had shown previously, using thia technique, that demented Alzheimer, non-DS patients have rates of lateral ventricular dilatation exceeding control rates. Our older (>35 years) nondemented DS subjects did not have a signilicantly higher mean rate of dilatation of the lateral ventricles than did the younger nondemented DS subjects, whereas the mean rate of dilatation in the older demented DS subjects was significantly greater 03 < 0.05) than in the young DS subjects. (An extended article describing these differences is in this issue of Neurology.8) It is true that Alzheimer neuropathology occurs in brains of DS subjects older than 35 years, but the amount and type of the pathology are quite variable. A prospective study of brains of 7 demented older DS subjects, for example, showed at least 20 neurofibrillary tangles and 20 senile (neuritic) plaques per high power field.3 In a retrospective study of older DS subjects with or without dementia, however, only 28 of 49 brains had this extent of ne~ropathology.~ Furthermore, several studies indicate that, in the normal course of DS, neurofibrillary tangles may appear in large numbers only 10 to 20 yeare after the appearance of large numbers of senile plaques.9 Accordingly, we recently suggested* that dementia and CT evidence of accelerated cerebral atrophy may appear only when tangles as well as p78ques proliferate, rather than plaques alone. These results, lh i ted by small numbers, suggeat that accelerated ventricular dilatation, beyond control rates, occurs only in DS subjects who become demented. It remains to be Been if these eubjecta also have large numbers of tangles as well as plaques. The heterogeneity of Alzheimer pathology and of dementia in the older DS population suggests that individual nondemented and demented DS subgroups, together with controls, should be examined thoroughly before the relations among dementia, brain atrophy, and Alzheimer neuropathology can be understood.