Pain in cancer and chronic non-cancer conditions: similarities and differences.

A conceptual model within which to view and compare cancer and chronic non-cancer pain is provided. Studies comparing the two are reviewed. Implications for deploying management and intervention strategies are then analyzed in terms of disease, cognitive-behavioral and social-contextual considerations.

The quota system in burn rehabilitation.

This article describes the quota system as a treatment for the helplessness behaviors and depressive symptoms that develop in some patients with burn injuries. With an A-B single-case design, the quota system was implemented for a patient who had sustained a particularly severe burn injury. A series of baseline behaviors were measured for 3 days, and then 80% of the patient's average performance on each of the targeted behaviors was computed and used as the initial quota value. The behavioral quotas were increased systematically and gradually by approximately 5% to 10% every day. The results suggest that the quota system may have been effective in decreasing an overall trend toward passivity, in increasing 3 of 4 targeted rehabilitation behaviors, and in reducing depressive symptoms in a patient with a particularly devastating injury.

On the nature of illness and disability: an editorial.

Issues underlying the rapid increase in assignment of disability to nonspecific low back pain are addressed. The central point of the discussion is that the healthcare system relies too exclusively on a biomedical perspective on pain and illness while failing to consider adequately environmental influences on symptom behavior and care seeking. Specific medical conditions with pathoanatomic findings observed are distinguished from nonspecific conditions in which those are lacking or only inferred. A biomedical model often suffices with specific conditions but, inherently, nonspecific conditions implicate the environment and social feedback. Impairment usually is defined in terms of biomedical issues. Disability, however, although often originating with impairment, is subject to major influence by patient effort and other considerations implicating the environment. In light of these issues in addition to reconsidering disability policy, attention also is directed to implications for the physician's role in implicitly encouraging patient perceptions of suffering as related inevitably to assumed underlying pathoanatomic factors.

The role of the upper airway in contributing to respiratory responses during experimental seizures in piglets.

Recent data demonstrating stimulation of respiration during seizures are at odds with the frequent clinical finding of respiratory impairment in patients with generalized seizures. To determine the role of the upper airway in contributing to these clinical observations, a study was performed in 12 weanling piglets. An arterial catheter and epidural electrodes were placed in ketamine-anesthetized piglets. In intact piglets, all airflow was measured through a snug-fitting nasal mask whereas pressure was measured with a subglottic catheter. Tracheostomized piglets had airflow and pressure measured at the trachea. Seizures were induced with i.v. injections of pentylenetetrazol. Peak inspiratory flow resistance was calculated by averaging three epochs of five to seven consecutive breaths. Epochs of greater than 20 s in duration with a tidal volume of < 10 mL were termed apnea. Apnea was considered central when airway pressure was > -2 cm H2O and obstructive when < -10 cm H2O. After 20 min of untreated seizures, intact piglets had significant respiratory and metabolic acidosis, whereas tracheostomized piglets had significant increases in Ve and mild metabolic acidosis. Apnea and obstruction were observed frequently in intact piglets. Resistance was unchanged during seizures in tracheostomized piglets, whereas a nearly 4-fold increase in inspiratory resistance was observed in intact piglets. We conclude that upper airway patency and resistances are important determinants of respiratory responses during generalized seizures in piglets.

Respiratory drive during status epilepticus and its treatment: comparison of diazepam and lorazepam.

In order to examine the respiratory effects of tonic-clonic seizures and their treatment with i.v. diazepam or lorazepam, we utilized a spontaneously breathing piglet seizure model. A tracheostomy, arterial catheter, and epidural electrodes were inserted and pigs were maintained under ketamine anesthesia. After baseline recordings, seizures were induced with a pentylenetetrazol (PTZ) bolus and a 20 min infusion (5-6 mg/kg/min). After 10 min of PTZ infusion, randomly assigned animals received diazepam (D; N = 7; 0.5 mg/kg), lorazepam (L; N = 7; 0.2 mg/kg), or 0.9% saline (C; N = 7; controls) by rapid peripheral vein injection. Minute ventilation (Ve), Pa(CO2), and the pressure change in response to airway occlusion at end-expiration (P0.1) were measured at standard intervals. All groups had comparable increases in respiratory drive during untreated seizures. Changes in Ve and P0.1 were reduced to at or below baseline values in groups D and L, but not C, from 2 to 45 min after treatment (P < 0.05). No significant changes were observed in Pa(CO2) after either intervention. Following anticonvulsants, the cumulative duration of seizures was significantly reduced in L and D groups, compared to C (P < 0.05). We conclude that increases in respiratory drive occur during tonic-clonic seizures induced with PTZ. Amelioration of seizure activity with lorazepam or diazepam results in a reduction in respiratory drive, but not respiratory failure, in this tracheostomized model.

On pain, illness and disability.

The biomedical perspective on management of pain, illness, and disability is analyzed and discussed. Pain and pain behavior are delineated. The distinction between acute and chronic pain, and the potential impact of social and environmental factors on pain behavior are reviewed. Distinctions between pain and suffering and between specific and non-specific pain are drawn and implications for the diagnostic process are considered. The importance of viewing clinical pain in biopsychosocial terms is emphasized and implications of that conceptual shift are reviewed. Attending to the social/environmental context in which patients function leads to an analysis of the social contract between individual and society. Implications of the concept of 'effort-related' on clinician as well as patient is considered. Clinician potential for stifling patient effort is reviewed. Finally implications of a biopsychosocial perspective on facilitation of return to work is considered.

Pain and suffering: what is the unit?

Nonspecific low back pain presents several problems to health care providers. Although the number of patients who are registered as disabled due to low back pain has dramatically increased in recent years, its incidence and severity remain fairly constant. The relationship between perceived backache and subsequent disability is not linear, and other factors may influence a patient's decision to seek help. These factors include the patient's psychological and emotional state, especially his or her past experiences, extant mood and anxiety about anticipated consequences. Physicians should not rely on a simple 'disease model' when treating low back pain but should try to identify the biopsychosocial factors involved and should understand that pain and suffering are not always synonymous.

The importance of placebo effects in pain treatment and research.

OBJECTIVE: To estimate the importance and implications of placebo effects in pain treatment and research from the existing literature, with emphasis on their magnitude and duration, the conditions influencing them, and proposed explanations. DATA SOURCES: English-language articles and books identified through MEDLINE (1980 through 1993) and PsycLIT (1967 through 1993) database searching, bibliography review, and expert consultation. STUDY SELECTION: Articles were included if they pertained to the review objectives. RESULTS: Placebo response rates vary greatly and are frequently much higher than the often-cited one third. Placebos have time-effect curves, and peak, cumulative, and carryover effects similar to those of active medications. As with medication, surgery can produce substantial placebo effects, and this possibility is commonly overlooked in case series reports on back surgery. Individuals are not consistent in their placebo responses, and a placebo-responder personality has not been identified. Models advanced to explain placebo effects emphasize the role of anxiety, expectations, and learning. CONCLUSIONS: Placebo effects influence patient outcomes after any treatment, including surgery, that the clinician and patient believe is effective. Placebo effects plus disease natural history and regression to the mean can result in high rates of good outcomes, which may be misattributed to specific treatment effects. The true causes of improvements in pain after treatment remain unknown in the absence of independently evaluated randomized controlled trials.

A piglet model of status epilepticus: comparison of cardiorespiratory and metabolic changes with two methods of pentylenetetrazol administration.

STUDY OBJECTIVE: Impaired cardiac and respiratory responses during active tonic-clonic convulsions (ictal periods) may contribute to complications during seizures. This study characterized physiologic parameters in two pentylenetetrazol (PTZ)-induced seizure models. PARTICIPANTS: Twelve spontaneously breathing piglets. INTERVENTIONS: Under ketamine anesthesia, a tracheostomy was performed, and an arterial catheter and epidural electrodes were inserted. Piglets received a PTZ bolus (100 mg/kg), with (six; 5 mg/kg/min) or without (six) an infusion of PTZ for 20 minutes. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases, mean arterial pressure, heart rate, tidal volume, and EEG waveforms were measured. Ictal periods had high-amplitude, synchronized EEG activity; interictal periods had EEG suppression. Seizure duration (24 +/- 3.5 versus 11 +/- 3.8 minutes; mean +/- SD) was significantly increased in the infusion group (P < .05). Significant increases in heart rate, minute ventilation, and base deficit plus decreases in pH occurred in both groups during seizures compared with baseline (P < .05). The duration and severity of metabolic acidosis were greater in the infusion group. During the first ten minutes of seizures, ten-second epochs were compared: beginning of ictal period, end of same ictal period, beginning of accompanying interictal period, and end of same interictal period. Respiratory rate decreased during initial interictal (65 +/- 40) more than latter ictal more than latter interictal period, compared with initial ictal period (194 +/- 65; P < .001). Tidal volume increased during latter ictal more than latter interictal more than initial ictal period (33 +/- 11), but the greatest increases occurred during initial interictal period (140 +/- 55; P < .001). CONCLUSION: This model demonstrates significant increases in the duration and various measures of seizure severity in piglets given a PTZ infusion compared with those receiving a bolus alone. Systematic alterations in respiratory but not cardiac responses occur during ictal-interictal cycling of PTZ-induced seizures.

Biodistribution and preclinical radioimmunotherapy studies using radiolanthanide-labeled immunoconjugates.

Lutetium-177 (177Lu), samarium-153 (153Sm), and yttrium-90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor-associated antigen TAG-72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab')2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA-DOTA. The authors also review the results of a biodistribution study comparing iodine-125-labeled and 177Lu-labeled CC49 sFv, and the use of 177Lu-CC+9 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab')2. Biodistribution data obtained in athymic mice bearing LS-174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab')2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal-labeled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu-CC49 was found to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 microCi. Dose fractionation experiments revealed that the mice tolerated 750 microCi (3 x 250 microCi, given weekly), whereas > 50% of the mice died after receiving a single administration of approximately 500 microCi. In isotype-matched control experiments, a large differential in the therapeutic effects was observed between 177Lu-labeled control antibody and CC49.

Central contribution to hypoventilation during severe inspiratory resistive loads.

OBJECTIVE: Recent observations suggest that central hypoventilation with slowing of respiratory frequency contributes to hypoventilation during severe inspiratory resistive loads. We carried out a study to further characterize this bradypneic response. DESIGN: Prospective, controlled laboratory study. SETTING: Basic science laboratory of a university hospital. SUBJECTS: Anesthetized adult cats (loading experiment n = 7, nonloaded hypercapnic controls n = 11). INTERVENTIONS: Experimental inspiratory loads increased transdiaphragmatic pressure to 75% of the maximum for each animal. Respiratory responses were observed at midrun or moderate conditions of respiratory insufficiency (defined as PaCO2 > or = 60 torr [> or = 8.0 kPa]) and failure (PaCO2 > or = 80 torr [> or = 10.6 kPa]). Nonloaded hypercapnic controls were studied with similar durations of exposure to CO2 in the same CO2 range. MEASUREMENTS: Inspiratory airflow, tidal volume, respiratory frequency, airway pressure, transdiaphragmatic pressure, transdiaphragmatic pressure response to phrenic nerve electrical stimulation, blood gas analysis. Severe inspiratory loads were applied to anesthetized adult cats to determine whether bradypnea could be observed in an anesthesized model that eliminated conscious responses. Experiments were performed in hyperoxic conditions to determine whether bradypnea develops in the absence of hypoxia. An additional control group was studied under hypercapnic conditions without loading to determine whether comparable hypercapnia is a sufficient stimulus to elicit bradypnea. RESULTS: From midrun until failure, minute ventilation decreased by 16% in loaded animals. Hypoventilation was associated with a decrease in respiratory frequency from 40.1 to 29.9 breaths/min, whereas tidal volume, spontaneous transdiaphragmatic pressure, and transdiaphragmatic pressure response to phrenic nerve electrical stimulation remained unchanged. Control animals had no significant reduction in ventilation or respiratory frequency over similar levels and durations of hypercapnia. CONCLUSIONS: Centrally mediated bradypnea contributed to hypoventilation in respiratory failure associated with inspiratory loading. Bradypnea preceded evidence of muscle fatigue. This change in respiratory cycle timing occurred under anesthesia, and thus, did not depend on conscious perception of dyspnea. Bradypnea does not depend on either hypercapnia or hypoxia.

Regulation of PaCO2 during rest and exercise: a modeling study.

A nonlinear mathematical model of the CO2 control system was used to examine a number of issues concerning the regulation of PaCO2 during rest and exercise. To gain insight to the regulatory properties of the respiratory system, the open loop gain (GL) and closed loop sensitivities SI = delta PaCO2/delta PICO2 and SV = delta PaCO2/delta VCO2 were calculated. GL indicates the ability of a control system to regulate the controlled variable, PaCO2 in the model. SI and SV represent the change in PaCO2 to unit changes in PICO2 and VCO2, respectively. Model predications were obtained for rest and various intensities of exercise for the following challenges to the respiratory system: (a) CO2 inhalation, (b) i.v. CO2 loading, (c) application of an external dead space, and (d) a shift in the resting operating point. Increasing exercise intensity produced a substantial decrease in GL and increase in SI consistent with the hypothesis that exercise degrades the ability of the respiratory system to regulate PaCO2. However, SV decreased indicating that the respiratory system would actually be better able to regulate PaCO2 if there were fluctuations in VCO2. Thus, GL does not completely describe the regulatory characteristics of the respiratory control system. It is demonstrated that the regulatory characteristics of the respiratory system as described by GL, SI, and SV are complex and depend on the nature of the challenge. Techniques for systematically describing the regulatory properties of the CO2 control system are described.

Analysis of urine samples from metastatic bone cancer patients administered 153Sm-EDTMP.

153Sm-EDTMP is currently undergoing clinical evaluation as a radiotherapeutic agent for the relief of pain associated with cancer metastatic to bone. These clinical studies have demonstrated biodistributions similar to those seen earlier in animals, namely, rapid clearance from blood, selective uptake in bone and in particular metastatic bone lesions. The radioactivity not deposited in bone is cleared through the kidneys into the urine. In this study, urine samples collected from 9 patients injected with 153Sm-EDTMP underwent complexation analysis via Pharmacia SP-Sephadex C25 cation exchange chromatography. The results showed 96.9 +/- 1.7% of the radioactivity in the urine to be present as a complex of 153Sm. An HPLC method was developed and it was demonstrated that different complexes of 153Sm could be separated. A non-radioactive analytical standard of the Sm-EDTMP chelate was synthesized, characterized and shown to have the same HPLC retention profile as the 153Sm-EDTMP drug product. HPLC analysis was performed on six urine samples and in each case a single radioactivity peak with an elution profile the same as that of a 153Sm-EDTMP standard was observed. These results indicate that the 153Sm-EDTMP chelate is excreted intact in the urine of patients.

Noninvasive monitoring of respiratory volume. Experimental evaluation of a breath monitoring device.

The authors studied the accuracy of the noninvasive breath monitor (Voltek Enterprise, Willowdale, Ontario, Canada) in predicting the tidal volumes in five healthy human volunteers. The signals of the breath monitor were compared with the volumes estimated by a calibrated pneumotachograph. The results show that the breath monitor is considerably accurate and can be accepted as a reliable device for clinical applications.

Development of a piglet model of status epilepticus: preliminary results.

STUDY OBJECTIVE: Ventilation frequently is impaired during prolonged clinical seizures and their treatment. In a pilot study, respiratory, metabolic, and hemodynamic variables were studied during induced seizures in a lightly anesthetized, spontaneously breathing piglet model. PARTICIPANTS: Weanling, mixed-breed domestic piglets. INTERVENTIONS: Piglets were instrumented with a tracheostomy, arterial catheter, and epidural electrodes. Conditions included hyperoxia, normothermia, and ketamine maintenance infusion throughout recordings. After baseline recordings, 2 mg/kg IV bicuculline was administered. For further model validation, piglets were randomized to infusions of diazepam (three), lorazepam (two), or saline (control; five) groups after ten minutes of untreated seizures. MEASUREMENTS AND MAIN RESULTS: Integrated tidal volume, respiratory rate, PaCO2, pH, arterial pressure, rectal temperature, heart rate, and bipolar EEG waveforms were recorded and compared at intervals for 60 minutes. Vigorous tonic-clonic seizures occurred in all piglets, confirmed by sudden synchronization and large-amplitude EEG waveforms. Increases in heart rate, arterial pressure, tidal volume, respiratory rate, PaCO2, minute ventilation, and base deficit occurred in all piglets during seizures as compared with baseline. Five minutes after bicuculline was administered, increases in minute ventilation (4.5 +/- 0.4 L/min at baseline to 13 +/- 2.1 L/min) were accounted for by increases in both tidal volume and respiratory rate. More abrupt decreases in respiratory rate were observed in anticonvulsant-treated piglets as compared with controls. The duration of continuous seizure activity (12 +/- 1.0 minutes versus 21 +/- 3.3 minutes; P < .05) was reduced in anticonvulsant-treated piglets. CONCLUSION: Significant increases in ventilation occur during generalized seizures in tracheostomized piglets given bicuculline. Diazepam and lorazepam infusions ameliorate seizure activity and suppress increases in respiratory rate but not minute ventilation as compared with controls. Problems with this model included baseline variability, temperature instability, and that direct respiratory stimulation from the convulsant agent may have occurred.

Differential metabolic patterns of iodinated versus radiometal chelated anticarcinoma single-chain Fv molecules.

Genetically engineered single-chain Fvs (sFv) are defined as recombinant proteins composed of a variable light chain amino acid sequence of an immunoglobulin tethered to a variable heavy chain sequence by a designed peptide. Previous studies using iodine-labeled sFv, derived from the anticarcinoma monoclonal antibody CC49, showed that the 125I-sFv could efficiently target antigen-positive tumors in a human tumor xenograft model while demonstrating rapid plasma clearance and minimal uptake in normal organs. One of the issues we raised in the analysis of the iodinated sFv metabolic studies was whether similar metabolic patterns would be observed if the sFv were labeled with a radiometal. In the studies reported here, 125I-CC49 sFv and 177Lu-CC49 sFv were co-injected in mice bearing antigen-positive carcinoma xenografts. Both sFv forms showed similar tumor targeting and plasma clearance pharmacokinetics. The 177Lu-sFv, however, showed a greater uptake in liver and spleen and a much higher uptake in kidney. These studies thus demonstrate that despite their small size (M(r) 27,000), the metal-chelated sFv shows a metabolic pattern very different than that of the iodinated sFv, which is most likely due to retention of the metal by organs metabolizing the sFv.

MMPI scale 3 as a predictor of back injury report: what does it tell us?

Items and selected subscales of Scale 3 (Hysteria) of the MMPI were examined to pinpoint personality or emotional factors predictive of back injury reports in an industrial setting. Data were derived from a previous prospective-design study of back pain in volunteer hourly wage employees of an aircraft manufacturing company. After physical examination and completion of questionnaires pertaining to demographic, psychosocial (including the MMPI), and workplace factors, workers were followed for an average of 3 years. Those who subsequently reported back injury were compared with those who did not. In that study three variables predicted report of back injury, one of which was Scale 3 of the MMPI. Individual items, Ornduff et al. subscales of Psychological Denial and Body Concern, and the five Harris-Lingoes (1955) subscales of Scale 3 were analyzed. Three Harris-Lingoes subscales showed significant relationships to the criterion. Hy-3: Lassitude/Malaise; Hy-1: Denial of Social Anxiety; and, marginally, Hy-2: Need for Affection, significantly contributed to prediction effectiveness. Results and implications for the understanding of factors predicting back injury reports and for the medical evaluation of pain and the concept of pain are discussed.

A longitudinal, prospective study of industrial back injury reporting.

The authors prospectively evaluated 3020 volunteers of the Boeing-Everett plant to assess risk factors that predispose workers to file industrial back injury claims. During four years of follow-up observation, more than 279 subjects reported acute back problems. The effect of the only predictive physical variable was explainable by a history of medical treatment. The most predictive individual factors were (1) job task dissatisfaction and (2) distress as reported on Scale 3 of the Minnesota Multiphasic Personality Inventory (MMPI). This data perhaps explains why the focus on purely physical and injury-related factors has met with little success in dealing with what has become the most expensive orthopedic problem. Clinically, nonphysical factors that significantly impact the reporting of back injuries may also affect patients' responses to medical treatment.