Elyad Davidson

Preoperative cardiac events in elderly patients with hip fracture randomized to epidural or conventional analgesia.

Background Perioperative myocardial ischemia occurs in 35% of unselected elderly patients undergoing hip fracture surgery. Perioperative epidural analgesia may reduce the incidence of adverse cardiac events. Methods The effect of early administration of epidural analgesia during the stressful presurgical period, on preoperative cardiac events was evaluated in a prospective randomized study in 68 patients with hip fractures who either had known coronary artery disease or were at high risk for coronary artery disease. On admission to the emergency room, patients were assigned to receive a usual care analgesic regimen (intramuscular meperidine, control group, n = 34) or continuous epidural infusion of local anesthetic and opioid (epidural group, n = 34). Monitoring in the preoperative period included a preoperative history and physical examination, daily assessment of cardiac adverse events, serial electrocardiograms, cardiac enzymes, and pain scores. Results Preoperative adverse cardiac events were significantly more prevalent in the control group compared with the epidural group (7 of 34 vs. 0 of 34;P = 0.01). Adverse cardiac events included fatal myocardial infarction in three, fatal congestive heart failure in one, nonfatal congestive heart failure in one, and new onset atrial fibrillation in two. The incidence of intraoperative and postoperative adverse cardiac events was similar for the two groups. The significant difference between groups in the incidence of preoperative cardiac events prompted interruption of the study after the planned interim analysis. Conclusions The authors’ data indicate that compared with conventional analgesia, early administration of continuous epidural analgesia is associated with a lower incidence of preoperative adverse cardiac events in elderly patients with hip fracture who have or are at risk for coronary artery disease. Preoperative epidural analgesia may be advantageous for this surgical population.

A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia

Background:Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans. Methods:A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/[(NH4)2SO4)]medium > 1,000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4°, 21°, and 37°C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and “empty” liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test. Results:The mean large multivesicular vesicle size was 2,439 ± 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4°C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor “empty” liposomes produced analgesia. Conclusions:This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.

Somatostatin receptors on peripheral primary afferent terminals: Inhibition of sensitized nociceptors

&NA; Somatostatin (SST) is in primary afferent neurons and reduces vascular and nociceptive components of inflammation. SST receptor (SSTR) agonists provide analgesia following intrathecal or epidural administration in humans, but neurotoxicity in the central nervous system (CNS) has been reported in experimental animals. With the rationale that targeting peripheral SSTRs would provide effective analgesia while avoiding CNS side effects, the goals of the present study are to investigate the presence of SSTRs on peripheral primary afferent fibers and determine the behavioral and physiological effects of the SST agonist octreotide (OCT) on formalin‐induced nociception and bradykinin‐induced primary afferent excitation and sensitization in the rat. The results demonstrate that: (1) SSTR2as are present on 11% of peripheral primary afferent sensory fibers in rat glabrous skin; (2) intraplantar injection of OCT reduces formalin‐induced nociceptive behaviors; (3) OCT reduces, in a dose‐dependent fashion, responses to thermal stimulation in C‐mechanoheat sensitive fibers; and (4) OCT reduces the responses of C‐mechanoheat fibers to bradykinin‐induced excitation and sensitization to heat. Each of these actions can be reversed following co‐injection of OCT with the SSTR antagonist cyclo‐somatostatin (c‐SOM). Thus, activation of peripheral SSTRs reduces both inflammatory pain and the activity of sensitized nociceptors, avoids deleterious CNS side effects and may be clinically useful in the treatment of pain of peripheral origin.

Methadone is safe for treating hospitalized patients with severe pain.

PurposeMethadone is still regarded as a second line opioid for patients suffering from severe pain, and is rarely used in hospitalized patients. The infrequent use of methadone is probably due to its long plasma half-life that could lead to accumulation and toxicity. In the present study we report that clinically effective analgesic doses of methadone, given either epidurally or orally, can be used safely for prolonged treatment in hospitalized patients.Clinical featuresOver a five-year period we administered methadone at Hadassah Hospital in Jerusalem to 3,954 in-patients with severe pain, 12% of whom were younger than 17 yr. Satisfactory pain relief was recorded in more than 85% of the patients. None of the patients treated with oral methadone developed serious side effects. Three patients, treated with epidural methadone (0.09%), developed a clinically significant respiratory depression. In all three cases, epidural pump failure or pump misprogramming resulted in methadone overdose. None of the children or adults treated with methadone developed addiction during hospitalization.ConclusionBased on its analgesic properties and marked safety profile, we suggest that methadone could be added to the analgesic armamentarium of in-hospital health-care providers. Moreover, methadone could serve as the opioid of first choice in some inpatient populations.RésuméObjectifLa méthadone est toujours considérée comme un opioïde mineur dans ies cas de douieurs intenses. Elle est rarement prescrite aux patients hospitalisés. Cette situation est sans doute reliée à sa longue demi-vie plasmatique qui peut entraîner accumulation et toxicité. Nous montrons ici que des doses anaigésiques efficaces de méthadone, administrées par voie épidurale ou orale, peuvent être utilisées sans danger comme traitement prolongé de patients hospitalisés.Eléments cliniquesPendant cinq ans, nous avons administré de !a méthadone pour douleurs intenses à 3 954 patients hospitalisés au Hadassah Hospital de Jérusaiem. Parmi eux, 12 % avaient moins de 17 ans. L’analgésie a été satisfaisante chez plus de 85 % des patients. Aucun effet secondaire important n’a été rapporté avec l’usage de la méthadone orale. Trols patients traités avec la méthadone épidurale (0,09 %) ont subi une dépression respiratoire significative. Une défaillance de la pompe épidurale ou une erreur de programmation avaient alors provoqué des surdoses de méthadone. Aucun enfant ou adulte traité avec la méthadone n’est devenu dépendant du médicament pendant l’hospitalisation.ConclusionÉtant donné ses propriétés analgésiques et son remarquable profil d’lnnocuité, nous croyons que la méthadone pourrait s’ajouter à l’arsenal thérapeutique des patients hospitalisés. Elle peut aussi servir d’opioïde de premier choix chez certains patients hospitalisés.

Pulse oximeter perfusion index as an early indicator of sympathectomy after epidural anesthesia.

Background: The pulse oximeter perfusion index (PI) has been used to indicate sympathectomy‐induced vasodilatation. We hypothesized that pulse oximeter PI provides an earlier and clearer indication of sympathectomy following epidural anesthesia than skin temperature and arterial pressure.

Photoplethysmographic measurement of changes in total and pulsatile tissue blood volume, following sympathetic blockade

Epidural anaesthesia, used for pain relief, is based on blocking the sensory and the sympathetic nerves in the lower part of the body. Since the sympathetic nervous system regulates blood vessel diameter, the sympathetic block is also associated with several haemodynamic changes. In the current study photoplethysmography (PPG) was measured on toes and fingers of patients undergoing epidural anaesthesia. Three parameters, which are related to the change in total and pulsatile tissue blood volume, were derived from the PPG baseline and amplitude. All parameters showed statistically significant increase in the toes after the sympathetic block, indicating higher arterial and venous blood volume and higher pulsatile increase in the arterial blood volume (higher arterial compliance) in the toe. These haemodynamic changes originate from the lower tonus of the arterial and venous wall muscles after the sympathetic block. In the fingers the PPG parameters based on the change in PPG amplitude decreased after the sympathetic block, indicating lower compliance. The measurement of the haemodynamic changes by PPG enables the assessment of the depth of anaesthesia, and can help control the adverse effects of the blockade on the vascular system.

The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study.

Objectives:The objective of this prospective, open-label study was to determine the long-term effect of medicinal cannabis treatment on pain and functional outcomes in participants with treatment-resistant chronic pain. Patients and Methods:The primary outcome was the change in the pain symptom score on the S-TOPS (Treatment Outcomes in Pain Survey—Short Form) questionnaire at the 6-month follow-up in an intent-to-treat population. Secondary outcomes included the change in S-TOPS physical, social, and emotional disability scales, the pain severity, and pain interference on the Brief Pain Inventory, sleep problems, and the change in opioid consumption. Results:A total of 274 participants were approved for treatment; complete baseline data were available for 206 (intent-to-treat), and complete follow-up data for 176 participants. At follow-up, the pain symptom score improved from median 83.3 (95% confidence interval [CI], 79.2-87.5) to 75.0 (95% CI, 70.8-79.2) (P<0.001). The pain severity score (7.50 [95% CI, 6.75-7.75] to 6.25 [95% CI, 5.75-6.75]) and the pain interference score (8.14 [95% CI, 7.28-8.43] to 6.71 [95% CI, 6.14-7.14]) improved (both P<0.001), together with most social and emotional disability scores. Opioid consumption at follow-up decreased by 44% (P<0.001). Serious adverse effects led to treatment discontinuation in 2 participants. Discussion:The treatment of chronic pain with medicinal cannabis in this open-label, prospective cohort resulted in improved pain and functional outcomes, and a significant reduction in opioid use. Results suggest long-term benefit of cannabis treatment in this group of patients, but the study’s noncontrolled nature should be considered when extrapolating the results.

Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases.

OBJECTIVE Pain relief is still inadequate in many hospitalized patients, especially children in whom suboptimal use of analgesic drugs is still common. In the past 2 years, oral methadone has been used extensively in our institution for treating children with persistent pain from cancer, burns, or trauma who were capable of oral intake and whose pain was not relieved by nonopioid medications. SETTING Tertiary university hospital. PATIENTS Of the 70 children treated thus far with oral methadone, five are described in the present report. MAIN OUTCOME MEASURE Pain relief, acceptability, and side effects of oral methadone in children with pain. RESULTS Treatment with oral methadone (0.1% in 10% glucose, dose range of 0.2-0.6 mg/kg/day) for time periods of up to 6 weeks resulted in a rapid onset and stable pain relief, with no major side effects. No adverse responses were encountered after discontinuation of treatment. In three of the children, a parent-controlled analgesia regimen was successfully employed. CONCLUSIONS Oral methadone can be recommended for babies and children who have severe pain that is not alleviated by nonopioid medications and who are capable of oral intake.

Perioperative management of chronic pain patients with opioid dependency.

Purpose of review In this article, we discuss the perioperative anesthesia and pain management of patients with chronic pain receiving chronic opioid administration. In our practice we may expect to be confronted with opioid-dependent patients in routine anesthesia practice and should acquire specific knowledge and skills to effectively manage the perioperative and acute pain management issues that arise. Recent findings The number of patients treated chronically with opioids has increased steadily over the past decade; currently about 10% of all chronic-pain patients are treated with opioids. As these patients are no longer confined to terminally ill cancer patients, growing numbers of these patients are facing surgical interventions. Summary In our clinical practice, we should employ multimodal pain management therapy by using an around-the-clock regimen of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, acetaminophen, and regional blockade. Dosing regimens should be individualized to optimize efficacy while minimizing the risk of adverse events.

Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic–pharmacodynamic study

BACKGROUND There are diverse reports concerning the single-nucleotide polymorphism (SNP) A118G in the gene coding for the mu-opioid receptor. This study assessed pharmacokinetic-pharmacodynamic relationships in patients with acute pain (water-immersed extracorporeal shock wave lithotripsy). METHODS Ninety-nine patients (ASA I-II, age 18-70) were assessed in this prospective observational study. Blinding was achieved by determining genotype only after the procedure. I.V. alfentanil was administered by patient-controlled administration (loading dose, 10 microg kg(-1); continuous infusion, 20 microg kg(-1) h(-1); bolus, 3 microg kg(-1); lockout time, 1 min); no other analgesic or sedating medication was used. RESULTS The allelic frequency was 15.2% in our population. The G118 SNP (AG/GG) was associated with a 27% increase in plasma alfentanil concentration (P=0.034), a 54% increase in alfentanil dose (P=0.009), a 47% increase in dose per kg body weight (P=0.004), a 55% increase in dose per kg corrected for stimulus intensity (P=0.002), a 112% increase in the numbers of attempted boluses (P=0.015), a 79% increase in the numbers of successful boluses (P=0.013), and a 153% increase in the numbers of failed boluses (P=0.042). Despite the increased alfentanil self-administration, the G118 SNP was associated with a 52% increase in verbal analogue pain scores over the same period of time (P=0.047). CONCLUSIONS We demonstrated increased opioid requirement for alfentanil in patients with the G118 SNP, who self-administered a higher dose, achieved higher plasma concentration, and yet complained of more severe pain. This observation suggests that G118 SNP impairs the analgesic response to opioids.