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Background: Combining neuraxial opioids and local anesthetics in acute pain results in improved duration of analgesia and reduced dosages and adverse effects. Although commonly used in intrathecal drug delivery systems (IDDS) for chronic pain, the effectiveness of this admixture has not been examined specifically in relation to patient-controlled intrathecal analgesia (PCIA)., Methods: IDDS-implanted chronic noncancer pain patients receiving opioids with bupivacaine (O + B) were randomized to receive either opioids without bupivacaine (O) or O + B in a double-blind manner, at IDDS refills, for one week and then crossed over to the other solution for another week. Primary outcome measures included numeric rating scale (NRS) pain scores before and within 30 minutes after PCIA boluses. Secondary outcome measures included average NRS scores and functional outcome measures., Results: Seventeen patients were enrolled, and 16 patients completed the study. There were no differences in NRS scores before and after PCIA boluses between the O and O + B conditions, though pain scores improved significantly (average decrease in NRS scores: O 1.81 ± 1.47 vs O + B 1.87 ± 1.40, P = 0.688). No differences were noted in speed of onset or duration of analgesia. Although more patients subjectively preferred the O + B treatment, the difference was not statistically significant. No differences were noted in secondary outcome measures, with the exception of global impression of change having higher scores in O compared with O + B., Conclusions: Acutely removing bupivacaine from a chronic intrathecal infusion of opioids and bupivacaine in patients with chronic noncancer pain did not adversely affect PCIA effectiveness, nor did it affect speed of onset or duration of effect. These findings are divergent from those in acute pain and may have to do with study conditions and pain phenotypes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The local anesthetic bupivacaine is a common analgesic adjuvant medication used in combination with opioids in intrathecal drug delivery systems (IDDSs). While the acute effects of spinal bupivacaine injection on blood pressure (BP) have been studied, there is a dearth of data regarding long-term effects of continuous intrathecal bupivacaine infusion., Materials and Methods: A retrospective review of all noncancer pain patients receiving bupivacaine through IDDSs from January 2013 to November 2017 was performed. Blood pressure values before implantation, and after implant at the 1-week, 3-month, 6-month and 1-year time points are recorded as well as corresponding bupivacaine and opioid doses in the IDDS., Results: Eighty-two patients were included in the study; median patient age was 64 years and intrathecal catheter tips were located predominantly in the lower thoracic spine. Significant decreases in systolic blood pressure (SBP) and mean arterial pressure (MAP) relative to baseline occurred in patients receiving chronic lower thoracic intrathecal bupivacaine delivery at 3, 6, and 12 months post-implant (-12.96 ± 18.21; p < 0.001 and - 6.38 ± 12.04; p < 0.001, respectively). The only significant decrease in DBP was observed at 1 year post-implant (-3.09 ± 11.76; p < 0.05). Similar decreases in BP values occurred in patients with or without hypertension., Conclusions: Long-term thoracic intrathecal infusion of bupivacaine likely exerts a lowering effect on BP, primarily because of a significant decrease in SBP. This effect is likely due to efferent sympathetic blockade by bupivacaine., (© 2019 International Neuromodulation Society.)

Objectives: Intrathecal (IT) trial is a prognostic interventional pain management procedure employed to determine the potential success of treating intractable pain with an implantable infusion device system. There is a dearth of data regarding trials with continuous infusion of combination therapy (e.g. opioid combined with local anesthetic). The objective of the this study was to determine the overall outcomes of continuous infusion IT trials and factors influencing long-term success of IT therapy in patients with chronic intractable pain post-laminectomy., Materials and Methods: This is a retrospective analysis of all patients with lumbar failed back surgery syndrome (FBSS) who were trialed with a combination of hydromorphone and bupivacaine with a temporary externalized IT catheter from March 2007 to June 2014., Results: From a cohort of 62 patients fulfilling the inclusion criteria, 54 (87.10%) patients had successful IT trials. No significant differences were found between successful and failed trial patients with regards to age, sex, pre-trial pain numeric rating scale scores, pre-trial morphine equivalent daily dose, or trial dosages. Significant positive correlations were found between pretrial oral opioid intake and end of trial hydromorphone dose and hydromorphone dose escalation at 12 months and 24 months., Conclusions: Patients with refractory low back pain due to FBSS who underwent successful combination IT trial with hydromorphone and bupivacaine infused through a temporary IT catheter had significantly improved pain intensity scores following permanent implant. Higher pre-trial MEDD was correlated with higher trial and post-implant opioid doses and higher rates of opioid dose escalation post-implant., (© 2017 International Neuromodulation Society.)

Background and Objectives: Intrathecal (IT) drug delivery systems (IDDSs) have been valuable in managing refractory chronic cancer and noncancer pain for more than 3 decades. These devices, time tested and overall reliable, have lately been noted at this institution to cease infusing unexpectedly. If not immediately recognized and rectified, this abrupt malfunction may lead to significant patient harm., Methods: A series of 13 patients from 1 academic center whose Medtronic SynchroMed II pumps malfunctioned from 2013 to 2015 is described. Data from the patient population with regard to variables that may increase the rate of IDDS malfunction are analyzed. The risk factors for IDDS malfunction, Medtronic-issued recalls, and current literature on IT device failure are reviewed., Results: The total prevalence of device motor stall among the population of this institution is 9.03%. The incidence rate of IDDS failure is calculated at 0.04 device failures per patient per year. Increased length of time from implant was the only statistically significant (P = 0.00009) risk factor for device failure identified in this population. Dysfunction in the motor gear train was found after destructive analysis of several devices in this series., Conclusions: Higher rates of device failure are associated with the use of off-label IT drugs. However, device failure may still occur while infusing only approved medications. Implanted patients should be properly informed and educated to differentiate and recognize the critical error alarm of their device as well as the signs and symptoms of IT medication overdose and withdrawal.

Human melanoma cells were treated in culture with the histamine (H2) agonist S-(3-(N-N-dimethylamino)propyl)isothiourea (dimaprit), a partial agonist, S-(2-(N,N-dimethylamino)ethyl)-isothiourea (nordimaprit), and two analogues of nordimaprit, S-(2-(N,N-diethylamino)ethyl)isothiourea (DENOR) and S-(2-(N,N-diisopropylamino)ethyl)isothiourea (DINOR), to investigate the effects on toxicity and tyrosinase activity. Cell survival studies showed highest toxicity in the constitutively pigmented human melanoma cell line MM418, DINOR being the most effective agent. Toxicity was not blocked by the H2 antagonist cimetidine. Dimaprit and its derivatives decreased tyrosinase activity in the amelanotic human melanoma cell line MM96E and inhibited expression of a melanosomal antigen. Loss of tyrosinase activity could be prevented by cimetidine and ranitidine, an H2 antagonist. Although the tyrosinase activity in MM418 cells was much more resistant to inhibition by these agents compared with that in MM96E cells, prolonged growth in the presence of non-toxic levels of DINOR caused a decrease in tyrosinase activity and subsequent depigmentation. Ultrastructural examination of the depigmented cells showed a decrease in the number of melanized melanosomes and the appearance of premelanosomes. These results indicate that bulky substituents on the tertiary amine group in nordimaprit significantly enhance potency for depigmentation and cell killing but only the former effect is mediated by the H2 receptor.

In cultured human melanoma cells, histamine H1 (mepyramine) and H2 receptor antagonists (cimetidine, ranitidine, impromidine) increased tyrosinase activity, whereas H2 agonists (dimaprit, nordimaprit) decreased activity. Mixtures of agonist and antagonist either decreased or increased tyrosinase activity, depending on the relative concentrations of each drug. Nordimaprit, the most effective inhibitor, lowered tyrosinase activity significantly within 36 h and caused a slower loss of tyrosinase protein as judged by reactivity with two monoclonal antibodies. Prolonged treatment of a melanotic cell line with nordimaprit led to complete loss of pigment, with no loss of the 56-kDa melanosomal antigen 1C11. Cells remained amelanotic for 8 weeks after removal of the drug and, even after 26 weeks, melanin content and tyrosinase expression and activity had not fully recovered. Nordimaprit increased the rate of degradation of tyrosinase and of nordimaprit binding proteins. Whereas nordimprit did not directly inhibit tyrosinase, lysates of treated cells contained an inhibitory activity that partitioned approximately equally across a 10-kDa ultrafiltration membrane. Overall, these results showed that melanogenesis can be controlled via histamine receptors, the mechanism for the H2 agonist nordimaprit consisting of three components: induction of a tyrosinase inhibitor, increased degradation of tyrosinase, and long-term down-regulation of tyrosinase expression.