New developments in epidural anesthesia and analgesia.

Several recent advances in epidural anesthesia and analgesia have been reviewed. Perhaps the most exciting area of anticipated future developments relates to the continued development of novel analgesic agents and new epidural delivery systems. There appears to be some movement toward an increased use of intrathecal or peripheral neural blockade techniques for some clinical situations where epidural anesthesia and analgesia have been previously used; however, the ability to provide anesthesia and analgesia to relatively large areas of the body with a single injection or continuous catheter technique without the associated risks of dural puncture and intrathecal catheter placement will continue to assure epidural anesthesia and analgesia techniques a prominent role in anesthesia and pain management.

Lateral cervical epidural catheter placement for continuous unilateral upper extremity analgesia and sympathetic block.

BACKGROUND AND OBJECTIVES: The use of the laterally directed cervical epidural catheter for the treatment of acute and chronic pain has not been previously described. We have used this technique in a series of 30 patients to produce unilateral upper extremity analgesia and sympathetic block. We present a case report of a patient treated with this technique and a description of the technique and results from the series. METHODS: We placed an epidural catheter at the C6-7 vertebral interspace and directed the needle bevel and catheter to the affected side in a woman with a history of complex regional pain syndrome of the right upper extremity. RESULTS: We were able to show a unilateral block with this technique by anatomic parameters (unilateral contrast dye spread), physiologic parameters (unilateral Horner's syndrome), and symptomatic parameters (unilateral, subjective neural block). Although 1 patient treated with this technique had bilateral effects, no patient has had a predominant block on the contralateral side and there have been no complications. CONCLUSIONS: This case report shows results typical of this series of 30 patients. In this series, the laterally directed cervical epidural catheter was an effective technique to produce continuous unilateral analgesia and sympathetic block. Key Words: Analgesia (epidural), Autonomic nerve block, Reflex sympathetic dystrophy, Postoperative pain.

A comparison of the analgesic efficacy of 0.25% levobupivacaine combined with 0.005% morphine, 0.25% levobupivacaine alone, or 0.005% morphine alone for the management of postoperative pain in patients undergoing major abdominal surgery.

UNLABELLED: We compared the relative efficacy of the combination of the single-isomer local anesthetic levobupivacaine and the opioid analgesic morphine versus both drugs alone for postoperative epidural analgesia after major abdominal surgical procedures. Thoracic epidural anesthesia was produced and maintained with levobupivacaine 0.75% in combination with general inhaled anesthesia without opioids. Patients were randomized to one of three postoperative treatment groups: 1) a combination of levobupivacaine 0.25% and morphine 0.005%; 2) levobupivacaine 0.25%; or 3) morphine 0.005%. Postoperatively, all epidural infusions were commenced at a rate of 4 mL/h. Patients could receive a 4 mL-bolus dose and an increase in the epidural infusion rate by 2 mL/h on request for supplemental analgesia. Patients were also allowed ketorolac as a supplemental analgesic at any time after the first analgesic request. Patients in the combination group had longer times to request for supplemental analgesia as compared with the levobupivacaine only group (P < 0.05) and a trend toward longer time to request as compared with the morphine only group (P = 0.066). Patients in the combination group had lower visual analog scale pain scores at rest and activity at 4 and 8 h and fewer requests for supplemental ketorolac (P < 0.05). In conclusion, this study demonstrates a significant improvement in postoperative analgesic efficacy with the combination of levobupivacaine and morphine for continuous epidural analgesia after major abdominal surgical procedures. IMPLICATIONS: A significant improvement in postoperative analgesic efficacy is demonstrated with the thoracic epidural administration of the combination of the single-isomer local anesthetic levobupivacaine 0.25% and morphine 0.005% in patients after major abdominal surgical procedures as compared with either drug used alone.

An investigation of the neurophysiologic mechanisms of tourniquet-related pain: changes in spontaneous activity and receptive field size in spinal dorsal horn neurons.

BACKGROUND AND OBJECTIVES: Several theories have been proposed for the pain resulting from the nerve compression and ischemia associated with maintaining the inflation of a pneumatic tourniquet on an extremity. This investigation observes changes in the spontaneous activity and receptive field (RF) size of spinal dorsal horn neurons during tourniquet-related nerve compression and ischemia. METHODS: Forty-eight pentobarbital-anesthetized rats were prepared for single-unit spinal dorsal horn cell recording utilizing an in vivo extracellular technique. Cells were characterized as either low threshold mechanoreceptor (LTM) neurons, wide dynamic range (WDR) neurons, or high threshold nociresponsive (NR) neurons based on their response to light touch (brush), non-noxious pressure, or noxious pinch. Receptive fields were carefully mapped. A 1 x 9 cm pneumatic tourniquet (Hokanson, Inc., Seattle, WA) was then applied to the animals' hind limb thigh and inflated to 300 mm Hg for 60 minutes. Throughout the 60-minute tourniquet inflation period, spontaneous activity, cell firing rate response characteristics, and RF size were carefully monitored. RESULTS: Twenty-three cells in 20 animals were characterized and monitored: 8 LTM, 6 WDR, and 9 NR neurons. Receptive fields were distal to the tourniquet cuff for 16 cells and proximal for 7 cells. Low threshold mechanoreceptor neurons demonstrated little spontaneous activity prior to tourniquet inflation in the absence of RF stimulation. The RF size for all LTM neurons decreased or became silent during the tourniquet inflation period. The RF size increased in two of six WDR neurons with two cells demonstrating a progressive increase in intermittent spontaneous firing during the tourniquet inflation period. Receptive field size increased in five of five NR neurons with RF located proximal to the tourniquet cuff from 29 +/- 10 mm2 to 54 +/- 30 mm2 (RF area 1.9 +/- 0.7; t = 2.7, P = .03). All five of these NR neurons also demonstrated an increase in spontaneous activity at 37 +/- 14 minutes of tourniquet inflation which continued throughout the remainder of the tourniquet inflation period (P < .05). CONCLUSIONS: The results of this study indicate that nerve compression and ischemia results in block of input to LTM neurons having RFs distal to the tourniquet cuff and an increase in spontaneous activity and expansion of the RFs of NRs, especially those with RFs located proximal to the tourniquet. Increases in spontaneous firing activity and expansion of the RFs of nociresponsive dorsal horn neurons receiving input from primary afferent nociceptors proximal to the tourniquet may explain, in part, the neurophysiologic mechanism of tourniquet-related pain.

The neurophysiologic mechanisms of tourniquet pain. The activity of neurons in the rostroventral medulla in the rat.

BACKGROUND: Tourniquet pain frequently complicates the use of pneumatic tourniquets during surgical procedures involving the extremities. The mechanisms of tourniquet pain are not understood and therefore the treatment is nonspecific. An animal model was sought to provide an ethical means to study the neurophysiologic and neuropharmacologic mechanisms of tourniquet pain. Neurons in the rostral ventromedial medulla are involved in the nociceptive-and circulatory-responsive neuronal networks. The goal of this study was to determine the activity of neurons in the rostral ventromedial medulla in response to the maintenance of tourniquet inflation in the rat as a component of an investigation of the neurophysiologic mechanisms of tourniquet-induced pain. METHODS: In 18 male, pentobarbital-anesthetized rats, heart rate, systolic blood pressure (SBP), and cell firing rates (CFR) of nociceptive-responsive rostral ventromedial medulla neurons, characterized as having an OFF or ON cell response to noxious heat, were monitored. CFR was monitored continuously at baseline, during an IV infusion of phenylephrine sufficient to increase SBP by 50%, during the application of a pneumatic tourniquet to the hind limb thigh and inflated to 300 mmHg for a period of 60 min, and during a 30-min recovery period. RESULTS: Phenylephrine-induced hypertension resulted in an increase in OFF CFR. Maintenance of tourniquet inflation resulted in a progressive decrease in OFF CFR and a progressive increase in ON CFR. An increase in SBP in response to tourniquet pain paralleled the changes in CFR. Mean SBP at 5 min preinflation, 5 min postinflation, 55 min postinflation, and 10 min postdeflation were 101 +/- 11, 103 +/- 9, 118 +/- 14, and 103 +/- 12 mmHg, respectively. CONCLUSIONS: The changes in SBP and CFR observed during tourniquet inflation were consistent with previously reported responses to nociceptive stimuli. Phenylephrine-induced hypertension caused an opposite effect on the CFR of rostral ventromedial medulla neurons as compared with a noxious stimulus such as heat or maintenance of tourniquet inflation. This experimental design is presented as an animal model to study the neurophysiologic and neuropharmacologic aspects of tourniquet pain.

Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics.

BACKGROUND: Development of tolerance to opioid analgesics occurs often in patients with cancer-related pain. Cross-tolerance among opioid analgesics provides the physician with a major management problem. Incomplete cross-tolerance among opioid analgesics has been demonstrated to occur in animals and humans. The current study provides clinical evidence of the incomplete cross-tolerance of methadone with a number of mu-opioid agonist analgesics in patients with advanced cancer-related pain. RESULTS: Patients presented in the current study had cancer-related pain refractory to other mu--opioid receptor agonist analgesics as evidenced by inadequate analgesia despite escalation of opioid dose. All patients were adequately managed by conversion of their opioid dose to methadone. Additionally, the dose of methadone required to establish and maintain analgesia in these patients was modest compared with previous opioid dose requirements. CONCLUSIONS: Methadone is a potent opioid analgesic that demonstrates incomplete cross-tolerance with other mu-opioid receptor agonist analgesics. Conversion of the opioid-tolerant patient with cancer-related pain to methadone may represent an important therapeutic option in the management of patients with this difficult problem.

Tourniquet pain: the response to the maintenance of tourniquet inflation on the upper extremity of volunteers.

This investigation examined the effect of three factors--tourniquet width, tourniquet inflation pressure, and application of the tourniquet to the left or right extremity--on the intensity of tourniquet pain and duration of tourniquet inflation, as well as the circulatory effects associated with maintenance of inflation of a pneumatic tourniquet on an upper extremity of 12 healthy, unmedicated volunteers. All subjects manifested a time-dependent circulatory response to maintenance of tourniquet inflation, characterized by increases in heart rate and systolic and diastolic blood pressure. The mean duration of tourniquet inflation was 34 +/- 13 minutes (mean +/- SD). No difference was demonstrated with respect to the width of the tourniquet, the tourniquet inflation pressure, or the application of the tourniquet to the left or right extremity on the intensity of pain or the duration of tourniquet inflation.

Response to maintenance of tourniquet inflation in a primate model.

Several theories have been proposed, but the etiology and pathway of neural transmission for the sensation of tourniquet pain remain unknown. This study was designed to observe the circulatory response and to measure the stress response markers associated with maintenance of tourniquet inflation in an anesthetized primate model. Eight African Green monkeys (Cercopithecus aethiops) were anesthetized, and heart rate (HR) and systolic and diastolic blood pressure (SBP and DBP) were measured every five minutes. In each animal, a control trial without tourniquet inflation was compared to an experimental trial with tourniquet inflation on the left lower extremity to 300 mmHg for a period of 90 minutes. After maintenance of tourniquet inflation for a period of 30-45 minutes, each animal demonstrated a gradual, progressive increase in HR, SBP and DBP as compared to preinflation baseline values (p less than 0.05). An increase in serum cortisol and plasma norepinephrine was demonstrated to correlate with the circulatory response in this model. The results of this study suggest that the circulatory response to maintenance of tourniquet inflation in this animal model may be mediated by a neurohumoral response to tourniquet pain and that an animal model may be appropriate for further studies into the etiology and neural pathways associated with the sensation of tourniquet pain.

Stability of methadone hydrochloride in 0.9% sodium chloride injection in single-dose plastic containers.

The stability of methadone hydrochloride in 0.9% sodium chloride injection in flexible polyvinyl chloride containers was studied. Commercially available methadone hydrochloride 20 mg/mL and 25-mL single-dose bags of 0.9% sodium chloride injection were used. Six samples each were prepared at methadone hydrochloride concentrations of 1, 2, and 5 mg/mL. The solutions were stored at room temperature and were not protected from light. Immediately after preparation and after two, three, and four weeks of storage, each of the 18 samples was divided into three aliquots, each of which was analyzed in duplicate for methadone hydrochloride concentration by gas chromatography. There was less than 10% change in methadone hydrochloride concentration in any sample throughout the four-week study period. Methadone hydrochloride at concentrations of 1, 2, and 5 mg/mL prepared in commercially available flexible polyvinyl chloride containers of 0.9% sodium chloride injection and stored at room temperature without deliberate protection from light is stable for at least four weeks.

Recovery of morphine from a controlled-release preparation. A source of opioid abuse.

MS-Contin (Purdue-Fredrick, Norwalk, CT) is a controlled-release preparation of morphine sulfate that has demonstrated efficacy in the management of chronic cancer pain problems. It has recently come to the attention of the authors that MS-Contin represents a potential source of opioid abuse through the extraction and intravenous injection of the morphine from this preparation. The authors describe a simple aqueous extraction method that was used to quantitatively determine the extent to which morphine could be obtained from MS-Contin tablets.

The correlation between predicted and measured patient specific analgesic concentrations after intravenous titration: a guide for initial maintenance requirements with methadone.

The relationship between the analgesic methadone concentrations measured and those predicted using a pharmacokinetic approach were assessed in 22 patients referred for long-term management of severe pain with intravenous methadone. Five milligrams of methadone were administered IV every 10 minutes until the patient reported a visual analog scale (VAS) pain score of less than or equal to 2. Initial maintenance infusion rates were chosen based on the number of 5 mg doses required to produce satisfactory analgesia. Overall, the methadone concentrations predicted using pharmacokinetic modeling were in excellent agreement with those actually measured. Over 95% of the variance in the data was explained using this model (r2 = 0.9704). Using the rapid titration paradigm described here, one can obtain a reasonable estimate of patient specific analgesic (target) concentration as well as initial infusion requirements for methadone.

Epidural opioid analgesia.

Epidural opioid analgesia has become an important therapeutic technique in the management of acute pain and has been demonstrated to be superior or equal to other parenteral opioid techniques (intramuscular, intravenous, PCA) with less associated sedation and significantly smaller doses of drugs. Beneficial therapeutic effects of epidural opioids as a result of improved analgesia include improvement in pulmonary function, modification of the endocrine-metabolic stress response, improvement in time to ambulation, decreased morbidity, and shorter hospital stay. The epidural administration of opioids is associated with potential side effects and complications, the most serious potential side effect being that of respiratory depression. This, as well as most of the other potential medication-related side effects associated with epidural opioid analgesia, is for the most part also associated with opioid analgesia provided by other routes of administration. These potential problems either occur rarely, or are controllable or preventable with appropriate patient selection and management. The potential benefits to the critical care patient as a result of the superior analgesia and reduced systemic effects associated with epidural opioid analgesia represent distinct medical and economic advantages, compared to conventional analgesic techniques.