James C. Eisenach

Polyanalgesic consensus conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

Background.  Expert panels of physicians and nonphysicians in the field of intrathecal therapies convened in 2000 and 2003 to make recommendations for the rational use of intrathecal analgesics based on the preclinical and clinical literature known up to those times. An expert panel of physicians convened in 2007 to update previous recommendations and to form guidelines for the rational use of intrathecal opioid and nonopioid agents.

phase I Safety Assessment of Intrathecal Neostigmine Methylsulfate in Humans

Background In dogs, sheep, and rats, spinal neostigmine produces analgesia alone and enhances analgesia from alpha2 ‐adrenergic agonists. This study assesses side effects and analgesia from intrathecal neostigmine in healthy volunteers. Methods After institutional review board approval and informed consent, 28 healthy volunteers were studied. The first 14 volunteers received neostigmine (50–750 micro gram) through a #19.5 spinal needle followed by insertion of a spinal catheter. The remaining 14 volunteers received neostigmine through a #25 or #27 spinal needle without a catheter. Safety measurements included blood pressure, heart rate, oxyhemoglobin saturation, end‐tidal carbon dioxide, neurologic evaluation, and computer tests of vigilance and memory. Analgesia in response to ice water immersion was measured. Results Neostigmine (50 micro gram) through the #19.5 needle did not affect any measured variable. Neostigmine (150 micro gram) caused mild nausea, and 500–750 micro gram caused severe nausea and vomiting. Neostigmine (150–750 micro gram) produced subjective leg weakness, decreased deep tendon reflexes, and sedation. The 750‐micro gram dose was associated with anxiety, increased blood pressure and heart rate, and decreased end‐tidal carbon dioxide. Neostigmine (100–200 micro gram) in saline, injected through a #25 or #27 needle, caused protracted, severe nausea, and vomiting. This did not occur when dextrose was added to neostigmine. Neostigmine by either method of administration reduced visual analog pain scores to immersion of the foot in ice water. Conclusions The incidence and severity of these adverse events from intrathecal neostigmine appears to be affected by dose, method of administration, and baricity of solution. These effects in humans are consistent with studies in animals. Because no unexpected or dangerous side effects occurred, cautious examination of intrathecal neostigmine alone and in combination with other agents for analgesia is warranted.

severity of acute pain after childbirth, but not type of delivery, predicts persistent pain and postpartum depression

Abstract Cesarean delivery rates continue to increase, and surgery is associated with chronic pain, often co‐existing with depression. Also, acute pain in the days after surgery is a strong predictor of chronic pain. Here we tested if mode of delivery or acute pain played a role in persistent pain and depression after childbirth. In this multicenter, prospective, longitudinal cohort study, 1288 women hospitalized for cesarean or vaginal delivery were enrolled. Data were obtained from patient interviews and medical record review within 36 h postpartum, then via telephone interviews 8 weeks later to assess persistent pain and postpartum depressive symptoms. The impact of delivery mode on acute postpartum pain, persistent pain and depressive symptoms and their interrelationships was assessed using regression analysis with propensity adjustment. The prevalence of severe acute pain within 36 h postpartum was 10.9%, while persistent pain and depression at 8 weeks postpartum were 9.8% and 11.2%, respectively. Severity of acute postpartum pain, but not mode of delivery, was independently related to the risk of persistent postpartum pain and depression. Women with severe acute postpartum pain had a 2.5‐fold increased risk of persistent pain and a 3.0‐fold increased risk of postpartum depression compared to those with mild postpartum pain. In summary, cesarean delivery does not increase the risk of persistent pain and postpartum depression. In contrast, the severity of the acute pain response to childbirth predicts persistent morbidity, suggesting the need to more carefully address pain treatment in the days following childbirth.

Epidural Clonidine Treatment for Refractory Reflex Sympathetic Dystrophy

BackgroundIntraspinally administered α2-adrenerglc agonists may relieve pain in sympathetically maintained pain (SMP) syndromes, such as reflex sympathetic dystrophy (RSD), by spinal, peripheral, and central nervous system actions. This study examined analgesic efficacy and side effects of epidurally administered clonidine in patients with severe, refractory RSD. MethodsTwenty-six patients with severe chronic pain consistent with RSD were studied in a randomized, blinded, placebo-controlled design. Cervical or lumbar epidural catheters were inserted for patients with upper or lower extremity RSD, respectively, and patients received, in random order on three consecutive days, epidural injection of clonidine, 300 or 700 μg, or placebo. Pain (by visual analog score (VAS) and McGill Pain Questionnaire), sedation, blood pressure, and heart rate were monitored at specified Intervals for 6 h after injection. Patients who responded to clonidine, but not placebo, then entered a trial of open-label, continuous epidural infusion of clonidine (10–50 μg/h). ResultsClonidine, but not placebo, caused pain relief, sedation, and decreased blood pressure and heart rate after bolus epidural injection. The smaller clonidine dose (300 μg), produced pain relief and decreases in blood pressure and heart rate similar to those of the 700 μg dose, but with less sedation. Epidural clonidine was infused for a mean of 43 days in 19 patients at a mean rate of 32 μg/h for sustained analgesia. ConclusionsTransdermal clonidine has been demonstrated to produce analgesia in the area surrounding its application site in patients with SMP. The current study indicates that extensive analgesia may be obtained by epidural administration. Sedation and hypotension may limit bolus epidural clonidine administration for RSD. The role for chronic epidural Infusion of clonidine has not yet been established.

Animal models and the prediction of efficacy in clinical trials of analgesic drugs : A critical appraisal and call for uniform reporting standards

a Pain Research, Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital Campus, 369 Fulham Road, London SW10 9NH, UK b Mari Lowe Centre for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010, USA c Department of Anesthesia, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, USA d Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland e Pfizer Global Research and Development, Sandwich CT13 9NJ, UK f Department of Psychology, McGill University, 1205 Dr. Penfield Avenue, Montreal, Que., Canada H3A 1B1 g Bitop AG, Stockumerstr. 28, 58453 Witten, Germany

Multifactorial Preoperative Predictors for Postcesarean Section Pain and Analgesic Requirement

Background: The study aimed to determine predictive factors for postcesarean pain and analgesia using an assessment of pain threshold and suprathreshold thermal stimuli as well as degree of somatization and anxiety. Methods: Thirty-four healthy parturients scheduled for cesarean delivery under subarachnoid anesthesia were enrolled. Preoperative thermal pain threshold, intensity, and unpleasantness to heat stimuli applied to arm and lower back, State Trait Anxiety Inventory, and patient expectation for postoperative pain and need for analgesia were assessed. After surgery, overall, resting, and movement pain and analgesic consumption were recorded. Prediction of pain and analgesic use outcomes was made by principal component factor analysis, followed by stepwise linear regression. Results: Resting pain was predicted by two factors, thermal pain and unpleasantness and patient expectation (r2 = 0.26, P < 0.01), evoked pain by thermal pain threshold in the back (r2 = 0.20, P < 0.009), composite pain by thermal pain and unpleasantness and preoperative blood pressure (r2 = 0.28, P < 0.008), intraoperative analgesic need by preexisting pain (r2 = 0.22, P < 0.006), recovery room analgesia by thermal pain threshold and State Trait Anxiety Inventory (r2 = 0.27, P < 0.01), and total analgesic need by State Trait Anxiety Inventory (r2 = 0.22, P < 0.01). These models predicted the upper twentieth percentile of composite pain scores and analgesic requirement with sensitivity of 0.71 to 0.80 and specificity of 0.76 to 0.80. Conclusions: The authors’ results suggest a meaningful combination of preoperative patient responses from physical and psychological tests yields a valid multifactorial predictive model for postoperative pain and analgesic requirement with significant improvements over individual predictive variables.

Epidural clonidine analgesia following surgery: phase I.

Epidurally administered clonidine has been reported to produce postoperative analgesia. To assess the efficacy, safety, and appropriate dose of epidural clonidine for postoperative analgesia, clonidine (range, 100-900 micrograms in 100-micrograms increments) was injected in 22 patients following abdominal surgery or total knee arthroplasty (TKA). Clonidine produced analgesia, as measured by change in verbal pain scores and supplemental iv morphine usage. The largest doses examined (700-900 micrograms) produced complete pain relief for 5.0 +/- 0.8 h (mean +/- SEM; range 2-11 h), without other sensory or motor blockade. Clonidine also produced dose dependent decreases in blood pressure, being less following small (100-300 micrograms) and large (700-900 micrograms) doses than following intermediate (400-600 micrograms) doses. Six patients required iv ephedrine for treatment of blood pressure decrease of greater than 30%. Clonidine decreased heart rate 10-30% and produced transient sedation. Oxyhemoglobin saturation, serum glucose, and arterial blood gas tensions were not altered by clonidine, whereas there was a small (28%) dose-independent decrease in serum cortisol following clonidine injection. Clonidine was absorbed in a dose-dependent manner into the systemic circulation, with plasma concentrations 0.1-3.3 ng/ml 1 h following injection. These results suggest that hemodynamic depression and short-lasting analgesia may limit the usefulness of bolus epidural clonidine analgesia in the postoperative setting.

Intrathecal Amitriptyline Acts as an N-Methyl-D-Aspartate Receptor Antagonist in the Presence of Inflammatory Hyperalgesia in Rats

Background Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N‐methyl‐D‐aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation‐induced neuroplasticity in hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation‐induced hyperalgesia in the rat.

Intrathecal Sufentanil Compared to Epidural Bupivacaine for Labor Analgesia

BackgroundAlthough intrathecal sufentanil has been reported to provide rapid-onset, complete analgesia lasting 1–3 h for the first stage of labor, no well-controlled double-blind study has compared this technique to the use of epidurally administered local anesthetics. MethodsFifty healthy parturient women requesting labor analgesia were studied. In a combined spinal-epldural technique, a spinal needle was inserted through the epidural needle before insertion of the epidural catheter. Patients were randomly assigned to receive either intrathecal sufentanil (10 μg) and epidural saline, or intrathecal saline and epidural bupivacaine (30 mg). Visual analog scores for pain, blood pressure, heart rate, sensory levels, and the incidence of nausea, pruritus, and motor blockade were recorded. ResultsPatients receiving intrathecal sufentanil had significantly lower visual analog pain scores at 5, 15, and 30 min after injection and a greater duration of analgesia before requesting additional medication (mean 123 vs. 68 min for those receiving bupivacaine; P < 0.05). These patients also experienced pruritus more frequently but motor blockade less frequently than patients receiving epidural bupivacaine. The groups exhibited dermatomal sensory deficits to pin prick as well as bradycardia and hypotension with equal frequency. The length of labor and type of delivery were similar between the groups. No patient experienced a post-dural puncture headache. ConclusionsThe rapid onset of analgesia and lack of motor blockade from intrathecal sufentanil injection may be advantageous in certain clinical situations. With this technique, however, pruritus is common; hypotension may occur; and extensive dermatomal spread suggests that early-onset respiratory depression could occur. Therefore, blood pressure and respiratory adequacy should be monitored if intrathecal sufentanil is used.

0.125% ropivacaine is similar to 0.125% bupivacaine for labor analgesia using patient-controlled epidural infusion.

We compared the effects of 0.125% ropivacaine with 0.125% bupivacaine in laboring patients using patient-controlled epidural analgesia (PCEA). Fifty-one ASA physical status I or II term parturients with functioning epidural catheters were randomized to receive ropivacaine or bupivacaine using a prospective, double-blind design. Basal infusions (6 mL/h) were supplemented with patient-controlled boluses (5 mL) every 10 min as required. For inadequate analgesia, patients were administered 10-mL boluses of study solution until comfortable. There were no differences in verbal pain scores, amount of local anesthetics used, sensory levels, motor blockade, labor duration, mode of delivery, side effects, or patient satisfaction between the two local anesthetics. We conclude that 0.125% ropivacaine and bupivacaine are clinically indistinguishable and are both highly effective for labor analgesia using PCEA. Implications: This study compared labor analgesia from 0.125% ropivacaine and 0.125% bupivacaine using patient-controlled epidural analgesia. We found no significant differences in local anesthetic use, analgesic characteristics, or side effects between 0.125% ropivacaine and 0.125% bupivacaine. We conclude that these two drugs are clinically indistinguishable at this concentration. (Anesth Analg 1998;86:527-31)