Posted February 11, 2015
Brian Williams, M.D., Michael Gold Ph.D., and Gerald Gebhart, Ph.D., University of Pittsburgh;
Chester Buckenmaier, M.D., Walter Reed National Military Medical Center

Drs. Brian Williams and Michael Gold Acute pain following traumatic injury is extremely common among wounded soldiers. Pain management on the battlefield may be critical for the safety of the wounded soldier and his/her comrades, as well as for the success of evacuation efforts. Additionally, untreated acute pain often serves as a predictor of chronic pain. The use of peripheral "nerve blocks" for pain management on the battlefield has a number of advantages over conventional opioid-based strategies, including (i) more effective pain relief, and (ii) the relative absence of potentially problematic side effects common to opioids, including altered mentation, somnolence and respiratory depression. However, the duration of nerve block associated with a single injection of a long-acting local anesthetic, such as bupivacaine or ropivacaine, is too short for the rapid evacuation plans currently employed by the military. Currently, continuous infusions of local anesthetics are widely used in clinical settings. Despite this, the technical difficulties associated with the use of catheter placement on the battlefield are very difficult. Thus, a single-injection nerve block that provides reliably greater than 24 hr duration would provide an important and efficient advance.

Using funding from a Fiscal Year 2009 Peer Reviewed Orthopaedic Research Program Translational Research Partnership Award, Drs. Brian Williams, Michael Gold, and Gerald Gebhart from the University of Pittsburgh partnered with COL Chester Buckenmaier at Walter Reed National Military Medical Center to identify a single-injection drug combination that effectively blocks acute post-traumatic pain over a long period of time without unwelcomed side effects. This group of collaborators hypothesized that a combination drug approach would allow for lower doses of each drug than if they were administered on their own, providing long-lasting pain relief and fewer undesirable side effects. The team tested varying concentrations and combinations of FDA-approved local anesthetics (e.g., bupivacaine [BPV], and ropivacaine [RPV]) in combination with other preservative-free medications that are FDA-approved for other indications (e.g., clonidine [CLON], buprenorphine [BPRE], dexamethasone [DEX], and midazolam [MDZ]), in an isolated rat sciatic nerve model to determine the dose-dependent effects of each drug on A- and C-fiber compound action potentials. Of the adjuvants tested, MDZ was of particular interest because it appeared to produce a pain-fiber selective block on its own, suggesting that in certain contexts might be more useful than local anesthetics, by blocking pain while preserving some motor control over the affected limb. However, because MDZ had a relatively narrow therapeutic window, producing toxicity at concentrations only slightly higher than those that produced nerve block, the group set out to determine whether or not different mechanisms were responsible for the nerve block and neurotoxic effects of the compound. Their results suggested that these two processes were, in fact dissociable, suggesting that it may be possible to produce even more effective and selective block of pain with minimal risk of side effects.

The group also conducted preclinical in vivo studies in rats to optimize the formulation of the drug combinations and also ensure that the individual drugs were chemically compatible and stable. Preliminary clinical data generated thus far show that the four-drug combination of CLON, BPRE, DEX, and BPV (BPV-CBD) is capable of providing pain relief for an average of 36 hours after joint replacement surgery, which is significantly longer than the 8- to 16-hour duration achieved with presently available nerve blocks using only single-injection BPV or RPV. In addition, preliminary clinical data show the 4-drug combination of MDZ-CLON-BPRE-DEX is associated with a mean of 33 hr duration for mild-to-moderate pain.

Dr. Williams and his partners are working to translate this promising new therapy into a definitive prospective randomized clinical trial to compare their four-drug combinations against the current gold standard - nerve block with plain local anesthetics - in veterans undergoing knee and hip joint arthroplasty. If successful, their research could lead to improved management of acute pain following battlefield injuries.


Williams BA, Butt MT, Zeller JR, et al. 2015. Multimodal perineural analgesia with combined bupivacaine-clonidine-buprenorphine-dexamethasone: Safe in vivo and chemically compatible in solution. Pain Medicine 16(1):186-98.

Williams BA, Ibinson JW, Mangione MP, et al. 2015. Research priorities regarding multimodal peripheral nerve blocks for postoperative analgesia and anesthesia, extracted from hospital quality data for over 1300 cases (2011-2014). Pain Medicine 16(1):7-12.

Williams BA, Ibinson JW, Mangione MP, et al. 2015. Clinical benchmarks regarding multimodal peripheral nerve blocks for postoperative analgesia: Observations regarding combined perineural midazolam-clonidine-buprenorphine-dexamethasone. Pain Medicine 16(1):1-6.

Yilmaz E, Hough KA, Gebhart GF, et al. 2014. Mechanisms underlying midazolam-induced peripheral nerve block and neurotoxicity. Regional Anesthesia and Pain Medicine 39(6):525-33.

Yilmaz-Rastoder E, Gold MS, Hough KA, et al. 2012. Effect of adjuvant drugs on the action of local anesthetics in isolated rat sciatic nerves. Regional Anesthesia and Pain Medicine 37(4):403-409.


Public and Technical Abstracts: Enhancing Post-Traumatic Pain Relief with Alternative Perineural Drugs

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