The relationship between the visual analog pain intensity and pain relief scale changes during analgesic drug studies in chronic pain patients.

BACKGROUND: Most analgesic drug studies in humans quantify drug action based on verbal reports of pain intensity and pain relief. Although measures of pain intensity and pain relief show a good overall correlation, it is not known if they relate to each other consistently over time Such consistency is necessary if both measures are used to depict analgesic drug action versus time. This study examined in chronic pain patients if the relationship between visual analog pain intensity and pain relief scores was consistent during two analgesic drug studies. METHODS: Data from two independently performed analgesic drug studies were analyzed using linear regression. Data were split into pain intensity and pain relief scores recorded before and after patients' experience of maximum analgesia (>90% of maximum pain relief). The slopes of the linear regression line depicting pain intensity versus pain relief scores before and after maximum analgesia were statistically compared. RESULTS: The slope of the linear regression line before and after maximum analgesia was significantly different in both drug studies (nonoverlapping 95% confidence intervals), -2.16+/-0.57 versus -1.05+/-0.10 and -1.47+/-0.26 versus -1.09+/-0.07, respectively. These results are compatible with the observation that patients indicating the same pain intensity before and after maximum analgesia reported a different magnitude of pain relief. CONCLUSIONS: The relationship between visual analog pain intensity and pain relief scores changed systematically during both analgesic drug studies. The authors hypothesize that patients' interpretation of the pain relief scale had changed during the studies and therefore suggest using the pain intensity scale to quantify analgesic drug action over time.

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

BACKGROUND: Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). METHODS: The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. RESULTS: The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. CONCLUSIONS: Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.

Chronic pain.

Chronic pain is an emotional experience and is defined as pain lasting greater than six months. It is important to understand the neurophysiology of pain in order to treat it. Nociceptors in the periphery travel to the substantia gelatinosa of the spinal cord while secondary and tertiary afferents transmit information from the dorsal horn to the brain. Modification of pain information may take place in these ascending pathways or in descending pathways. Treatment of chronic pain is most successful when it is approached in a multidisciplinary fashion with the focus not only on treatment of underlying etiology, but also on the secondary impacts of pain on the patient's life. The management of chronic pain requires special expertise. Most of the experts in chronic pain assessment and management organize themselves into pain treatment centers. These centers vary widely in their approach to the problem. The most sophisticated is a multidisciplinary center that is university-based and includes teaching and research. Treatment of chronic pain includes a variety of medications, psychological support, and rehabilitation. Multidisciplinary pain management is also an integral part of the palliative care and hospice concept used to treat cancer pain.

Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain.

OBJECTIVE: The objective was to assess the analgesic, antihyperesthesic, and anti-allodynic properties of SNX-111 in neuropathic pain. DESIGN: We describe a patient with refractory, severe deafferentation pain successfully treated with SNX-111 in an open-label, baseline-controlled Phase I/II trial. SETTING: The patient was hospitalized for treatment and observation. PATIENT: The patient was a 43-year-old man with intractable deafferentation pain of 23 years' duration secondary to brachial plexus avulsion. INTERVENTION: SNX-111, the first neuron-specific, N-type, voltage-sensitive calcium channel blocker developed for clinical use, was administered by continuous, constant-rate, intrathecal infusion via an indwelling cervical catheter. OUTCOME MEASURES: The primary outcome measures were the Visual Analog Scales of Pain Intensity (VASPI) and Pain Relief (VASPR). RESULTS: The patient experienced complete pain relief (VASPI = 0.0 cm and VASPR = 10.0 cm) with elimination of hyperesthesia and allodynia. CONCLUSIONS: SNX-111, administered intrathecally by continuous, constant-rate infusion, produced dose-dependent pain relief in a 43-year-old male patient with a 23-year history of intractable deafferentation and phantom limb pain secondary to brachial plexus avulsion and subsequent amputation. Dizziness, blurred vision, and lateral-gaze nystagmus were dose-dependent side effects that resolved with decreasing dose levels. Complete pain relief was achieved in this patient without side effects after dose adjustment. We conclude that SNX-111 is a potent analgesic, antihyperesthesic, and antiallodynic agent. Controlled studies of SNX-111 in patients with malignant and nonmalignant pain syndromes are warranted and are under way.

Derivation and cross-validation of pharmacokinetic parameters for computer-controlled infusion of lidocaine in pain therapy.

BACKGROUND: Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of the drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain. METHODS: Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micrograms.ml-1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model. RESULTS: The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micrograms.ml-1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters ( +/- population variability expressed as %CV) were estimated as follows: V1 0.101 +/- 53% 1.kg-1, V2 0.452 +/- 33% 1.kg-1, Cl1 0.0215 +/- 25% 1.kg-1.min-1, and Cl2 0.0589 +/- 35% 1.kg-1.min-1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%. CONCLUSIONS: Pharmacokinetic parameters for lidocaine were derived and administration was prospectively tested via computer-controlled infusion pumps for patients with chronic neuropathic pain. The estimated parameters performed well when tested prospectively. A second estimation step further refined the parameters and improved performance, as measured using internal cross-validation.

Morphine and hydromorphone epidural analgesia. A prospective, randomized comparison.

Because evidence from uncontrolled, unblinded studies suggested fewer side effects from epidural hydromorphone than from epidural morphine, we employed a randomized, blinded study design to compare the side effects of lumbar epidural morphine and hydromorphone in 55 adult, non-obstetric patients undergoing major surgical procedures. A bolus dose of epidural study drug was given at least 1 h prior to the conclusion of surgery, followed by a continuous infusion of the same drug for two postoperative days. Infusions were titrated to patient comfort. Visual analog scale (VAS) pain scores, VAS sedation scores, and subjective ratings of nausea and pruritus were assessed twice daily. The two treatments provided equivalent analgesia. Sedation scores and prevalence of nausea did not differ significantly between groups. Prevalence of pruritus, however, differed significantly on postoperative day 1, with moderate to severe pruritus reported by 44.4% of patients in the morphine group versus 11.5% in the hydromorphone group (P < .01). On post-operative day 2, reports of pruritus by patients receiving morphine remained higher than those among the hydromorphone-treated subjects, although this difference was no longer statistically significant (32% vs. 16.7%, P = .18). We conclude that lumbar epidural morphine and hydromorphone afford comparable analgesia, but the occurrence of moderate to severe pruritus on the first postoperative day is reduced by the use of hydromorphone.

Oxyhaemoglobin saturation following elective abdominal surgery in patients receiving continuous intravenous infusion or intramuscular morphine analgesia.

Oxygen saturation was continuously measured using computerised pulse oximetry for 8 h overnight pre-operatively and for the first 24 h postoperatively in 40 patients receiving intermittent intramuscular morphine or continuous infusion of morphine following elective upper abdominal surgery. The proportion of time with an oxygen saturation less than 94% was used as an index of desaturation. Patients receiving continuous infusion analgesia received a larger morphine dose and achieved better analgesia than the intramuscular group. Postoperatively, the duration of desaturation increased 10-fold over pre-operative values, 'intramuscular' patients spending 39.0% (SD, 37.0%) and 'continuous infusion' patients 40.0% (SD, 37.5%) of the time below 94% saturation. Although newer therapies (e.g. epidural analgesia and patient-controlled analgesia) are currently receiving greater attention, the sequelae of these more traditional analgesic techniques warrant further study.

Analgesia after cesarean delivery: patient evaluations and costs of five opioid techniques.

The study was designed to compare five opioid analgesic regimens administered after cesarean delivery in a routine hospital setting with respect to patients' perceptions of their pain relief and the impact of analgesic technique on recovery and hospital costs. After cesarean delivery, 684 patients received one of the following: epidural morphine, alone (EM,n = 128), or with fentanyl (EM + F,n = 245); subarachnoid morphine (n = 48); intramuscular meperidine (n = 165), or patient-controlled analgesia using meperidine (PCA, n = 98). On the first three postoperative days (Days 1-3; day of operation is Day 1) patients were surveyed regarding their impressions of their analgesia, the incidence of side effects, times to resume normal activities and satisfaction with their technique. Information regarding drug interventions and costs was obtained from anesthetic records and nursing charts. Patients receiving intramuscular and PCA opioids reported significantly more severe pain during the first 16 hours than those receiving intraspinal opioids (p less than 0.05); differences were minimal for the remainder of Day 1. Among the intraspinal groups, analgesia was best overall with EM; specifically, fentanyl did not decrease early postoperative pain. Analgesia with PCA and intramuscular opioids was similar during the first 16 hours; however, PCA patients felt they had less pain thereafter. Side effects were common in all intraspinal groups and were least frequent with PCA (p less than 0.05 versus all intraspinal groups). Times to sit, walk and drink were similar in all patients except those receiving intramuscular opioids after general anesthesia, who experienced a several-hour delay. Other aspects of recovery did not differ among the groups. Satisfaction parallelled pain relief and was better with intraspinal than with systemic opioids. Costs were greatest with PCA, although differences were small (less than 1%) relative to total hospital charges.

Continuous epidural hydromorphone for postthoracotomy pain relief.

Forty-four patients were treated with a continuous infusion of lumbar epidural hydromorphone (0.05%) after thoracic operations. Postoperatively, visual analog pain scores were obtained. On postoperative day 1 and 2, more than 90% of the patients experienced either no pain (visual analog pain scale = 0) or mild pain (visual analog pain score = 1 to 3) at rest. The incidence of side effects (hypoventilation, pruritus, and nausea) was less than reported with other epidurally administered opioids. Continuous infusion of lumbar epidural hydromorphone produced safe, predictable analgesia after thoracotomy.

Variables of patient-controlled analgesia. 3: Test of an infusion-demand system using alfentanil.

Patient-controlled infusion-demand analgesia was studied using alfentanil. We were unable to identify an optimal dose and administration rate; doses required range from 100 to 900 micrograms alfentanil. The mean concentration of alfentanil in blood associated with return of pain (i.e. immediately before demand) was 58 ng/ml on day 1 and 37 ng/ml on day 2. This difference was despite similar drug consumption on both days.

Oxyhemoglobin saturation following cesarean section in patients receiving epidural morphine, PCA, or im meperidine analgesia.

The frequency and severity of oxyhemoglobin desaturation was compared in 49 patients receiving epidural morphine, 5 mg (n = 21); patient-controlled analgesia (PCA) using meperidine (n = 20); or intramuscular (im) meperidine (n = 8) for postoperative analgesia following elective cesarean section performed with epidural anesthesia. Oxygen saturation (SpO2) was monitored for 24 h using a pulse oximeter; data were continuously collected and stored every 30 s via an interface connected to a computer. For analysis purposes, SpO2 was divided into five categories: 96-100%, 91-95%, 86-90%, 81-85%, and less than or equal to 80%. Although SpO2 remained above 95% for the majority of the monitored period, patients in all groups experienced periods of desaturation. PCA patients spent the longest cumulative time with SpO2 between 91 and 95%, 231 +/- 49 min (mean +/- SEM), compared with only 112 +/- 30 min and 152 +/- 42 min for the epidural and im groups, respectively (P less than 0.05 vs. epidural group). PCA patients also spent longest with SpO2 at 86-90% (19 +/- 10 min, vs. 6 +/- 3 and 0.5 +/- 0.3 min for the epidural and im groups, respectively), although this difference was not statistically significant. Severe desaturation episodes, defined as SpO2 less than or equal to 85% for more than 30 s, occurred in 71% of patients in the epidural group, 30% in the PCA group, and 63% in the im group (P less than 0.05 PCA vs. epidural and im).(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive measurement of femoral artery pressure for evaluating aortoiliac occlusive disease.

Femoral systolic pressures measured by a compression technique (FSCP), were compared with proximal thigh systolic pressures (PTSP), for evaluation of aortoiliac occlusive disease. In phase I FSCP were measured by compressing the artery with a pressure cuff rolled into a cylinder and using disappearance of the profunda femoris Doppler signal (FSCP-D), or flattening of thigh plethysmographic waveforms (FSCP-P), as sensors. In normal extremities the compression techniques yielded false high values. The mean ratio of FSCP-D to brachial systolic pressure, FSCP-D/BSP, was 1.25 +/- 0.06 and the mean FSCP-P/BSP was 1.37 +/- 0.15, a value approximately equal to the mean PTSP/BSP, 1.38 +/- 0.20. In patients with aortoiliac occlusive disease linear regression analysis revealed a good correlation between FSCP-D/BSP and direct intraoperative measurements of femoral/aortic systolic pressure, FSP/ASP, (R = 0.79 and R2 = 0.63), a fair correlation between FSCP-P/BSP and FSP/ASP (R = 0.49, R2 = 0.24) but a poor correlation between PTSP/BSP and FSP/ASP (R = 0.35, R2 = 0.12). In phase II studies a soft bladder was used for arterial compression. In normal extremities the mean FSCP-D/BSP was 1.07 +/- 0.06, close to the predicted normal value of 1.00. In a second group of patients with occlusive disease a better correlation was observed between values of FSCP-D/BSP and FSP/ASP (R = 0.91, R2 = 0.82), than any of the correlations of noninvasive measurements with direct intraoperative values of FSP/ASP obtained in the first phase of the study.