Oscar A. de Leon-Casasola

Opioid therapy and immunosuppression: a review.

The idea that opioids modulate the immune system is not new. By the late 19th century, Cantacuzene, used morphine to suppress cellular immunity and lower the resistance of guinea pigs to bacterial infection. While exogenous opioids mediate immunosuppression, endogenous opiates exert opposite actions. Acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity. Opiates behave like cytokines, modulating the immune response by interaction with their receptors in the central nervous system and in the periphery. Potential mechanisms by which central opiates modulate peripheral immune functions may involve both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. The presence of opioid receptors outside the central nervous system is increasingly recognized. Those receptors have been identified not only in peripheral nerves but also in immune inflammatory cells. The immunosuppression mediated by opiates may explain the increased incidence of infection in heroin addicts. Opiates may also promote immunodeficiency virus infection by decreasing the secretion of α and β chemokines (important inhibitory cytokines for the expression of HIV) and at the same time increasing the expression of chemoreceptors CCR5 and CCR3, coreceptors for the virus. The fact that peripheral immunosupression is mediated at least in part by opioid receptors located in the central nervous system and that intrathecally administered opioids do not exert the same immunosuppressive effects may have important clinical implications for those patients receiving long-term opioid therapy for malignant and nonmalignant pain.

Neurolytic superior hypogastric plexus block for chronic pelvic pain associated with cancer

&NA; Twenty‐six patients with extensive gynecologic, colorectal or genitourinary cancer who suffered uncontrolled, incapacitating pelvic pain were enrolled in this study during a 1‐year period. All the patients receiving oral opioids who developed poor pain response due to the progression of disease or untoward side effects necessitating other modes of therapy were eligible to participate. Bilateral percutaneous neurolytic superior hypogastric plexus blocks with 10% phenol were performed in every patient, 1 day after receiving successful diagnostic blocks using 0. 25% bupivacaine (BUP). All patients reported a visual analog pain score (VAPS) of 10 of 10 before the block. Eighteen patients (69%) had satisfactory pain relief (VAPS < 4 of 10): 15 (57%) after 1 block and 3 (12%) after a second block. The remaining 8 patients (31%) had moderate pain control (VAPS 4–7 of 10) after 2 blocks and received epidural bupivacaine‐morphine (BUP‐MS) therapy with good results. Both groups experienced significant reductions in oral opioid therapy after the neurolytic blocks. No additional blocks were required by patients who had a good response during a follow‐up period of 6 months. No complications related to the block were experienced by any patient. In conclusion, neurolytic superior hypogastric plexus block was both effective in relieving pain in 69% of the patients studied (95% confidence interval of 48–85%). Additional neurolytic blocks using higher volumes of the neurolytic agent may be needed in patients with extensive retroperitoneal disease, a group in whom moderate or poor results should be expected.

Postoperative Epidural Bupivacaine-Morphine Therapy Experience with 4,227 Surgical Cancer Patients

BackgroundWe prospectively studied surgical cancer patients who received epidural bupivacaine-morphine to determine perioperative morphine use, side effects, and complications. MethodsAll study patients received general-epidural anesthesia followed by epidural analgesia with 0.05% or 0.1% bupivacaine and 0.01% morphine at a rate of 5–10 ml · h−1 to keep the dynamic pain score at less than 5 (of 10). Patients were evaluated daily for pain relief, side effects, catheter migration, accidental removal, hypotension, respiratory rate, mental status changes, nausea and vomiting, and pruritus. ResultsOver 4 yr, 4,227 patients (61% women, aged 68 ± 24 yr) were studied. Lumbar epidural catheters (n = 2,248 or 53.18%) were used more frequently than thoracic catheters (n = 1,979 or 46.82%) (P < 0.00001). Most of the patients were discharged to the surgical wards after the procedures (n = 3,001, 71%). Those patients (n = 1,226, 29%) admitted to the surgical intensive care unit, spent 1.2 ± 0.8 days. Epidural catheter failure occurred in 283 (6.3%) patients. Length of epidural analgesia therapy was 6.3 ± 2.6 days. There were three cases (0.07%) of respiratory depression which were treated with oxygen, intravenous naloxone, and by stopping the epidural infusion for 6 h. Hypotension occurred in 126 patients (3%). There were no apparent cases of catheter migration to either the subdural or subarachnoid space. Nausea or vomiting occurred in 929 patients (22%). Pruritus occurred in 930 patients (22%). ConclusionsContinuous epidural analgesia with 0.05–0.1% bupivacaine and 0.01% morphine is an effective method of postoperative analgesia with a low incidence of side effects, that can be safely administered on the surgical wards with no special monitoring equipment.

Epidural Bupivacaine/Sufentanil Therapy for Postoperative Pain Control in Patients Tolerant to Opioid and Unresponsive to Epidural Bupivacaine/Morphine

BackgroundOpioids are thought to have equal analgesic effects when equivalent doses are used. However, sufentanil may achieve maximum effect while occupying fewer spinal opioid receptors (higher intrinsic efficacy). Therefore, sufentanil may be more effective than morphine when administered intraspinally in opioid-tolerant patients. MethodsThis study evaluated 20 chronic cancer pain patients who underwent abdominal surgery for tumor resection. All patients used large doses of morphine (> 250 mg/day-1) preoperatively for 3 months or longer. Intraoperatively, patients received combined general-epidural anesthesia with 0.5% bupivacaine and 0.02% morphine at 8 ml/h-1. Postoperative continuous epidural analgesia with 0.1% bupivacaine and 0.02% morphine at 5 ml/h-1 plus intravenous patient-controlled analgesia morphine (3 mg every 6 min) was given. Epidural infusions were increased every 30 min by 1 ml/h-1 to achieve a dynamic (during coughing) visual analog pain score (VAPS) of less than 5/10. If the desired VAPS was not achieved after 6 h or the epidural morphine infusion was increased to 2 mg/h-1, 50 μg of sufentanil in 10 ml of normal saline was given as an epidural bolus dose. The epidural infusion then was switched to 0.0002% sufentanil (2 μg/ml-1) and 0.1% bupivacaine (1 mg/ml-1) at 7 ml/h-1. Further titration to maintain a dynamic VAPS of less than 5/10 occurred every 4 h. ResultsMean preoperative daily oral morphine use was 380 ± 97 mg (range 290–490) for 4 ± 1 months. Before the switch to sufentanil, patients had received a mean maximum morphine dose of 8.8 ± 0.2 mg intraoperatively plus 9.0 ± 1.2 mg during 4.2 ± 0.3 h postoperatively (1.8 ± 0.4 mg/h-1), at which point VAPS ranged between 7–10/10. All patients experienced adequate analgesia within 1 h of starting sufentanil therapy. The mean sufentanil dose during the first 4 h of treatment was 17 ± 0.2 μg/h-1. At this time, VAPS ranged from 0–3/10. Satisfactory analgesia was achieved with sufentanil at a lower than a calculated equally potent dose of morphine (23 μg/h-1 vs. 17 μg/h-1, P < 0.01). Intravenous patient-controlled analgesia morphine requirements were also lower (7.8 mg/h-1 vs. 2.0 mg/h-1, P < 0.01). Length of morphine and sufentanil therapies were 5 ± 3 h and 10 ± 2 days, respectively. No patient experienced signs or symptoms of opioid withdrawal. ConclusionsThese results suggest that sufentanil can be used successfully in opioid-tolerant patients who do not experience adequate pain control in the early postoperative period despite a large dose of epidural morphine. Moreover, sufentanil should be considered an effective alternative therapy for postoperative pain control in chronic opioid users using high doses of oral opioids before surgical intervention.

Bowel function recovery after radical hysterectomies: thoracic epidural bupivacaine-morphine versus intravenous patient-controlled analgesia with morphine: a pilot study.

STUDY OBJECTIVE To determine if the use of continuous epidural bupivacaine-morphine in the perioperative period is associated with a significant decrease in the recovery time of postoperative ileus when compared with parenteral morphine administration. DESIGN Prospective (quality of analgesia) and retrospective (bowel function recovery), nonrandomized study. SETTING Inpatient gynecology-oncology patients at a university-affiliated tertiary cancer center hospital. PATIENTS 68 women who experienced uncomplicated radical hysterectomies for cancer. INTERVENTIONS Intraoperative epidural-general anesthesia or general anesthesia only was administered. Postoperative continuous epidural analgesia with bupivacaine-morphine and intravenous (IV) morphine via patient-controlled analgesia (PCA). Both forms of therapy were titrated to provide patients with a dynamic visual analog pain score of 5 or less on a 10-point scale throughout the study period. Patients were weaned from infusions when pain scores remained at less than 5 for 12 hours and no breakthrough medication was used. MEASUREMENTS AND MAIN RESULTS Rest and dynamic pain scores, time of first flatus, length of nasogastric therapy, time to solid food intake, daily and total morphine requirements and length of hospitalization were recorded. The epidural group required fewer days of nasogastric therapy (4 +/- 3 versus 8 +/- 2 days, p = 0,0001), tolerated solid foods sooner (6 +/- 2 versus 11 +/- 3 days, p < 0.0001), and had a shorter hospitalization time (10 +/- 3 versus 14 +/- 4 days, p = 0.0001) when compared with the PCA group. CONCLUSIONS The use of thoracic epidural bupivacaine-morphine results in a decrease in the duration of postoperative ileus, which was associated with earlier hospital discharge.

Opioids for chronic pain: new evidence, new strategies, safe prescribing.

In the United States, the prevalence and burden of chronic pain is large and still growing. Older adults (aged ≥65 years) make up a large portion of the population with chronic pain, and their presentation, diagnosis, and treatment tends to be more complicated because of age-related physiological changes and comorbidities. Guidelines on treating patients with severe back pain recommend opioids as an option for those who do not find adequate pain relief from acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). For older adult patients at higher risk for NSAID-related adverse effects, such as those who have gastrointestinal or cardiovascular disease, diabetes mellitus, or who are taking low-dose aspirin, opioids are recommended instead. Opioids may also be an appropriate option for patients with neuropathic pain who have not achieved adequate analgesia from maximum doses of first- and second-line antineuropathic agents. Still, opioids are not appropriate for all patients; rather, a differential diagnosis, consideration of other comorbidities, and the potential for opioid-related adverse effects and substance abuse are required to confirm the value of opioid treatment for each individual. For nonresponders to opioid therapy, opioid rotation should be considered before discontinuation is pursued.

Current developments in opioid therapy for management of cancer pain.

Pain remains a highly prevalent problem for patients with cancer and typically falls into one of 3 types: visceral, somatic, and neuropathic. A mechanistic, pathophysiologic approach to pain management involves a good assessment of the type of pain, followed by tailoring of the treatment based on the diagnosis. This pain management strategy can provide rapid pain control with a lower incidence of complications and side effects than other methods. Furthermore, pharmacogenetics may play an important role in individualizing therapies in the future, but for now this type of data offers explanations for phenomena commonly observed in clinical practice, such as (1) differences in individual analgesic and side-effect responses to various opioid agents, (2) incomplete cross-tolerance seen when switching between μ opioid analgesics, and (3) why opioid rotation can be beneficial for patients after an opioid therapy loses efficacy or becomes associated with intolerable side effects. Especially for difficult-to-manage pain patients, additions to the opioid analgesic armamentarium can potentially better individualize pain management, and provide another option to be used for opioid rotation. Among the most recent Food and Drug Administration–approved opioid analgesics for acute pain and persistent pain are oral immediate-release and extended-release formulations of oxymorphone, whereas for breakthrough pain, the ultrarapid-acting opioid, fentanyl effervescent buccal tablets, has newly been developed and indicated within the United States.

Research Gaps in Practice Guidelines for Acute Postoperative Pain Management in Adults: Findings From a Review of the Evidence for an American Pain Society Clinical Practice Guideline

UNLABELLED Acute postoperative pain is a common clinical condition that, when poorly controlled, can result in a number of significant negative consequences. The American Pain Society commissioned an evidence-based guideline on the management of postoperative pain to promote evidence-based, safe, and effective perioperative pain management. An interdisciplinary panel developed 31 key questions and inclusion criteria to guide the evidence review. Investigators reviewed 6556 abstracts from multiple electronic databases up to November 2012, an updated evidence review to October 2014, and key references suggested by expert reviewers. More than 800 primary studies not included in a systematic review and 107 systematic reviews were included. Despite a large body of evidence, a number of critical research gaps were identified where only low-quality or insufficient evidence was found to help guide clinical practice recommendations. This report identifies evidence gaps including optimal methods and timing of perioperative patient education, nonpharmacological modalities, combinations of analgesic techniques, monitoring of patient response to treatment, techniques for neuraxial and regional analgesia, and organizational care delivery models. Recommendations to help guide the design of future perioperative studies are offered. PERSPECTIVE Acute postoperative pain is a common clinical condition requiring an evidence-based, planned, and multimodal approach. Despite the plethora of published evidence, much of it is weak and key questions remain unanswered. Researchers are encouraged to work together to produce strong evidence to help guide clinical decisions in perioperative pain management.

Magnetic Resonance Imaging in Patients with Spinal Neurostimulation Systems

Background:The safety of performing magnetic resonance imaging (MRI) in patients with spinal cord stimulation (SCS) systems needs to be documented. A prospective in vivo study in patients with SCS, exploring the changes produced by MRI and the associated side effects, was performed. Methods:After ethics committee approval and patient consent, 31 consecutive patients with SCS at different spinal levels requiring a scheduled MRI evaluation were studied during an 18-month period. All MRIs were performed with a 1.5-T clinical use magnet and a specific absorption rate of no more than 0.9 W/kg. Frequency tables were used for the descriptive study, whereas comparative evaluations were made with the chi-square test for qualitative variables and single-factor analysis of variance for quantitative variables. Results:The mean patient age was 49 ± 9.5 yr; 67.7% were women (n = 21), and 32.3% were men (n = 10). None of the patients experienced hemodynamic, respiratory, or neurologic alterations. Reported changes were as follows: increased temperature in the generators area (n = 2, 6.5%); increased in the intensity of the stimulation (n = 1, 3.2%); impedance greater than 4,000 &OHgr; on several of the electrodes in the leads (n = 1, 3.2%); telemetry not possible (n = 2, 6.5%). Radiologic evaluation after MRI revealed no spatial displacements of the SCS leads in any case. Conclusion:Under the conditions of the described protocol, MRI in patients with SCS systems resulted in few complications. None of the recorded problems were serious, and in no case were patients harmed or the systems reprogrammed. Maximum patient satisfaction was reported in all cases.

New Developments in the Treatment Algorithm for Peripheral Neuropathic Pain

Neuropathic pain often imposes a substantial and unrelenting burden on those individuals who have it; single-agent analgesics typically only reduce pain at best. Worldwide, five sets of treatment recommendations offer insight into managing neuropathic pain, including two European guidelines, one Canadian, one Latin American, and another constructed under the auspices of the International Association for the Study of Pain (IASP). The analgesics common to these guidelines are topical lidocaine, secondary amine tricyclic antidepressants, serotonin and norepinephrine dual reuptake inhibitors, calcium channel α(2)-δ ligands, tramadol, and opioid antagonists. Still, significant knowledge gaps in the treatment of neuropathic pain conditions have hampered the development of algorithms and multimodal approaches. As the evidence base expands, the addition of new comparative trial data will further refine the development of new guidance for clinical management of neuropathic pain. New alternatives for managing neuropathic pain, such as the high-concentration capsaicin patch, will enlarge the treatment armamentarium and potentially impact therapeutic guidelines.