Timothy Furnish

Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study.

BACKGROUND: Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of <24 hours. A liposomal bupivacaine formulation (EXPAREL®, Pacira Pharmaceuticals, Inc., San Diego, CA), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration but not peripheral nerve blocks. METHODS: Bilateral single-injection femoral nerve blocks were administered in healthy volunteers (n = 14). For each block, liposomal bupivacaine (0–80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received 2 different doses, 1 on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. RESULTS: There were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04–0.14, P = 0.002) and tolerance to cutaneous current (−0.03 mA/mg, SE = 0.01, 95% CI, −0.04 to −0.02, P < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI, 43%–93%), block duration usually lasted much longer: for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%–100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%–100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, −0.27 to 0.39, P = 0.707). CONCLUSIONS: The results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.

Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence.

Cannabinoid compounds include phytocannabinoids, endocannabinoids, and synthetics. The two primary phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with CB1 receptors in the brain and peripheral tissue and CB2 receptors in the immune and hematopoietic systems. The route of delivery of cannabis is important as the bioavailability and metabolism are very different for smoking versus oral/sublingual routes. Gold standard clinical trials are limited; however, some studies have thus far shown evidence to support the use of cannabinoids for some cancer, neuropathic, spasticity, acute pain, and chronic pain conditions.

A randomized, triple-masked, active-controlled investigation of the relative effects of dose, concentration, and infusion rate for continuous popliteal-sciatic nerve blocks in volunteers

BACKGROUND It remains unknown whether local anaesthetic dose is the only factor influencing continuous popliteal-sciatic nerve block effects, or whether concentration, volume, or both exert an influence as well. METHODS Bilateral sciatic catheters were inserted in volunteers (n=24). Catheters were randomly assigned to ropivacaine of either 0.1% (8 ml h(-1)) or 0.4% (2 ml h(-1)) for 6 h. The primary endpoint was the tolerance to transcutaneous electrical stimulation within the tibial nerve distribution at hour 6. Secondary endpoints included current tolerance at other time points and plantar flexion maximum voluntary isometric contraction (22 h total). RESULTS At hour 6, tolerance to cutaneous stimulation for limbs receiving 0.1% ropivacaine was [mean (standard deviation)] 27.0 (20.2) vs26.9 (20.4) mA for limbs receiving 0.4% [estimated mean difference 0.2 mA; 90% confidence interval (CI) -8.2 to 8.5; P=0.02 and 0.03 for lower and upper boundaries, respectively]. Because the 90% CI fell within the prespecified tolerance ±10 mA, we conclude that the effect of the two concentration/volume combinations were equivalent. Similar negative findings were found for the secondary outcomes. CONCLUSIONS For continuous popliteal-sciatic nerve blocks, we found no evidence that local anaesthetic concentration and volume influence block characteristics, suggesting that local anaesthetic dose (mass) is the primary determinant of perineural infusion effects in this anatomic location. These findings suggest that for ambulatory perineural local anaesthetic infusion-for which there is usually a finite local anaesthetic reservoir-decreasing the basal rate while increasing the local anaesthetic concentration may allow for increased infusion duration without compromising postoperative analgesia. CLINICAL TRIAL REGISTRATION NCT01898689.

Chronic Opioid Use Following Surgery for Oral Cavity Cancer

Importance Opioid misuse and overuse has become an epidemic. Chronic opioid use among oral cavity cancer patients after surgery has not been described. Objectives To assess the prevalence of chronic opioid use in patients undergoing surgery for oral cavity cancer, and evaluate possible associated clinical factors; and the association between opioid use and survival. Design, Setting, and Participants For this retrospective cohort study of patients undergoing surgery for oral cavity cancer a consecutive sample of 99 patients between January 1, 2011, and September 30, 2016, were identified through the institutional cancer registry from a single academic center. Exposures Surgery for oral cavity cancer. Main Outcomes and Measures Chronic opioid use, defined as more than 90 days from surgery. Factors associated with chronic opioid use were investigated by univariable and multivariable logistic regression. The Kaplan-Meier method and Cox proportional hazards model were used to assess overall survival and disease-free survival. Results The mean (SD) patient age was 62.6 (14.3) years; 60 patients (60%) were male. Chronic opioid use was observed in 41 patients (41%). On multivariable logistic regression, preoperative opioid use (odds ratio [OR], 5.6; 95% CI, 2.2-14.3), tobacco use (OR, 2.8; 95% CI, 1.0-8.0), and development of persistence, recurrence, or a second primary tumor (OR, 2.8; 95% CI, 1.0-7.4) were associated with chronic opioid use. Among preoperative opioid users, estimated overall survival (hazard ratio [HR], 3.2; 95% CI, 1.4-7.1) was decreased, and chronic opioid use was associated with decreased disease-free survival (HR, 2.7; 95% CI, 1.1-6.6). Conclusions and Relevance In patients undergoing surgery for oral cavity tumors, the prevalence of chronic opioid use was considerable. Preoperative opioid use, tobacco use, and development of persistence, recurrence, or a second primary tumor were associated with chronic opioid use after surgery, and both preoperative and chronic opioid use were associated with decreased survival.

Lenalidomide and thalidomide in the treatment of chronic pain.

Introduction: The immunomodulatory and anti-inflammatory drug thalidomide was first introduced in 1957 as a sleep aid and treatment for morning sickness. It was subsequently removed from the market due to severe teratogenic side effects and then returned to the market as a treatment for myelodysplastic syndrome and multiple myeloma. Lenalidomide is an analog of thalidomide with similar efficacy but improved side-effect profile. There are reports and studies of both agents for the treatment of chronic pain, especially complex regional pain syndrome (CRPS). Effective medical and interventional therapies for CRPS are limited. The use of novel immunomodulatory and anti-inflammatory drugs such as thalidomide and lenalidomide may offer a new approach to the treatment of CRPS. Areas covered: The mechanism of action, adverse effect profile, and regulatory history of thalidomide and lenalidomide will be reviewed. The literature search for pain treatment includes case series and preliminary trials for CRPS, and case reports and case series for other chronic pain conditions. Expert opinion: Lenalidomide has a more favorable adverse effect profile compared to its parent compound thalidomide. Both agents, however, have significant potential adverse effects. Evidence of efficacy for chronic pain syndromes such as CRPS remains limited. Further studies are needed before these agents can be recommended for use in CRPS or other chronic pain syndromes.

Continuous Adductor Canal Blocks: Does Varying Local Anesthetic Delivery Method (Automatic Repeated Bolus Doses Versus Continuous Basal Infusion) Influence Cutaneous Analgesia and Quadriceps Femoris Strength? A Randomized, Double-Masked, Controlled, Split-Body Volunteer Study.

BACKGROUND:It remains unknown whether continuous or scheduled intermittent bolus local anesthetic administration is preferable for adductor canal perineural catheters. Therefore, we tested the hypothesis that scheduled bolus administration is superior or noninferior to a continuous infusion on cutaneous knee sensation in volunteers. METHODS:Bilateral adductor canal catheters were inserted in 24 volunteers followed by ropivacaine 0.2% administration for 8 hours. One limb of each subject was assigned randomly to a continuous infusion (8 mL/h) or automated hourly boluses (8 mL/bolus), with the alternate treatment in the contralateral limb. The primary end point was the tolerance to electrical current applied through cutaneous electrodes in the distribution of the anterior branch of the medial femoral cutaneous nerve after 8 hours (noninferiority delta: −10 mA). Secondary end points included tolerance of electrical current and quadriceps femoris maximum voluntary isometric contraction strength at baseline, hourly for 14 hours, and again after 22 hours. RESULTS:The 2 administration techniques provided equivalent cutaneous analgesia at 8 hours because noninferiority was found in both directions, with estimated difference on tolerance to cutaneous current of −0.6 mA (95% confidence interval, −5.4 to 4.3). Equivalence also was found on all but 2 secondary time points. CONCLUSIONS:No evidence was found to support the hypothesis that changing the local anesthetic administration technique (continuous basal versus hourly bolus) when using an adductor canal perineural catheter at 8 mL/h decreases cutaneous sensation in the distribution of the anterior branch of the medial femoral cutaneous nerve.

Medical Cannabis for Neuropathic Pain

Purpose of ReviewMany cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications. Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain.Recent FindingsWe examined current basic scientific research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain. These studies involved patients with diverse etiologies of neuropathic pain and included medical cannabis with different THC concentrations and routes of administration. Multiple RCTs demonstrated efficacy of medical cannabis for treating neuropathic pain, with number needed to treat (NNT) values similar to current pharmacotherapies.SummaryAlthough limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low-dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain. The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoid ratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain.

Risk of respiratory depression with opioids and concomitant gabapentinoids

Introduction The combination of opioids and central nervous system depressants such as benzodiazepines and barbiturates has an additive effect on the frequency of oversedation and respiratory depression requiring naloxone use in hospitalized patients. Gabapentinoids (gabapentin and pregabalin) are frequently prescribed with opioids for their opioid-sparing and adjuvant analgesic effects. There is limited literature on the risk of respiratory depression due to the combination of opioids and gabapentinoids requiring naloxone administration. Methods This retrospective study evaluated patients who were prescribed opioids and at least one dose of naloxone between March 1, 2014 and September 30, 2016. The primary objective of this study was to compare the frequency of respiratory depression among patients who received naloxone and opioids (non-gabapentinoid group) with those who received naloxone, opioids, and gabapentinoids (gabapentinoid group). Secondary objectives included comparing the association of oversedation, using the Pasero Opioid-induced Sedation Scale, and various risk factors with those in the gabapentinoid group. Results A total of 153 patient episodes of naloxone administration (102 in the non-gabapentinoid and 51 in the gabapentinoid groups) in 125 unique patients were included in the study. For the primary objective, there were 33 episodes of respiratory depression associated with the non-gabapentinoid group (33/102=32.4%) versus 17 episodes of respiratory depression with the gabapentinoid group (17/51=33.3%) (p=0.128). Secondary objectives showed a significant association between respiratory depression and surgery in the previous 24 hours (p=0.036) as well as respiratory depression and age >65 years (p=0.031) for patients in the non-gabapentinoid group compared to the gabapentinoid group. Conclusion There was no significant association of respiratory depression in the gabapentinoid group versus the non-gabapentinoid group. There was an increased risk of respiratory depression in the gabapentinoid group, specifically in patients who had surgery within the previous 24 hours.

Continuous Transversus Abdominis Plane Nerve Blocks: Does Varying Local Anesthetic Delivery Method-automatic Repeated Bolus Versus Continuous Basal Infusion-influence the Extent of Sensation to Cold?: A Randomized, Triple-masked, Crossover Study in Volunteers.

BACKGROUND: It remains unknown whether continuous or scheduled intermittent bolus local anesthetic administration is preferable for transversus abdominis plane (TAP) catheters. We therefore tested the hypothesis that when using TAP catheters, providing local anesthetic in repeated bolus doses increases the cephalad-caudad cutaneous effects compared with a basal-only infusion. METHODS: Bilateral TAP catheters (posterior approach) were inserted in 24 healthy volunteers followed by ropivacaine 2 mg/mL administration for a total of 6 hours. The right side was randomly assigned to either a basal infusion (8 mL/h) or bolus doses (24 mL administered every 3 hours for a total of 2 bolus doses) in a double-masked manner. The left side received the alternate treatment. The primary end point was the extent of sensory deficit as measured by cool roller along the axillary line at hour 6 (6 hours after the local anesthetic administration was initiated). Secondary end points included the extent of sensory deficit as measured by cool roller and Von Frey filaments along the axillary line and along a transverse line at the level of the anterior superior iliac spine at hours 0 to 6. RESULTS: Although there were statistically significant differences between treatments within the earlier part of the administration period, by hour 6 the difference in extent of sensory deficit to cold failed to reach statistical significance along the axillary line (mean = 0.9 cm; SD = 6.8; 95% confidence interval –2.0 to 3.8; P = .515) and transverse line (mean = 2.5 cm; SD = 10.1; 95% confidence interval –1.8 to 6.8; P = .244). Although the difference between treatments was statistically significant at various early time points for the horizontal, vertical, and estimated area measurements of both cold and mechanical pressure sensory deficits, no comparison remained statistically significant by hour 6. CONCLUSIONS: No evidence was found in this study involving healthy volunteers to support the hypothesis that changing the local anesthetic administration technique (continuous basal versus hourly bolus) when using ropivacaine 0.2% and TAP catheters at 8 mL/h and 24 mL every 3 hours significantly influences the cutaneous effects after 6 hours of administration. Additional research is required to determine whether changing variables (eg, local anesthetic concentration, basal infusion rate, bolus dose volume, and/or interval) would provide different results.

The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis:

Chronic opioid therapy for pain management is known to induce several endocrine changes. The authors examined the effect of testosterone supplemental therapy (TST) in patients with chronic, noncancer pain undergoing opioid therapy. It was hypothesized that treatment of opioid-induced hypogonadism (OIH) can reduce opioid requirements in patients suffering from chronic pain and approve their quality of life. Over 18 months period, patients with OIH were identified in a tertiary referral pain center, Numerical Rating Scale (NRS) pain scores and daily morphine equivalent dose (MED) were the primary outcomes measured. Data were collected and comparative analysis performed between men undergoing TST versus nontreatment group. Twenty-seven OIH patients (total testosterone <300 ng/dL) were identified during the study period. TST group consists of 11 patients, while non-TST group consists of 16 patients as control cohort. Mean patient age (55 and 54.4, p = .4) and basic metabolic index (28.5 and 31.9, p = .07) in TST and non-TST groups, respectively. Mean follow-up total testosterone (ng/dL) was significantly higher after TST compared with the non-TST group (497.5 vs. 242.4 ng/dL, p = .03). Median follow-up NRS was 0 and 2 in the TST and non-TST groups (p = .02). Mean MED (mg) decreased by 21 mg in TST group and increased by 2.5 mg in non-TST group (p < .05). This study reports that treatment of OIH with TST can reduce opioid requirements in men with chronic pain as quantified by MED. It also confirms previous reports on the potential effects of OIH and that TST is effective in correcting opioid-induced endocrine abnormalities.