After completion of training I came to Stanford University in 1998. Since that time I have been involved in a number of clinical and research activities. I oversee the Pain Service at the Palo Alto VA hospital where I am involved in the care of patients with both acute and chronic pain. I am active both in the clinic and on a number of committees dedicated to improving pain management for veterans. Much of my remaining time is spent supervising a research laboratory. There we are pursuing several projects related to the questions of why pain sometimes becomes chronic after injuries and why opioids lose their effectiveness over time when used to treat chronic pain. We would like to find ways to maximize functional recovery after surgery and other forms of trauma while minimizing the risks of analgesic use. This work involves local, national and international collaborations.

Academic Appointments

Administrative Appointments

  • Director of Pain Service, VAPAHCS (1998 - Present)
  • Vice-Chair for Research, Department of Anesthesia, Perioperative Medicine and Pain (2012 - Present)

Boards, Advisory Committees, Professional Organizations

  • Handling Editor, Anesthesiology (2013 - Present)
  • Chairman, VAPAHCS Research and Development Committee (2013 - Present)
  • Member, Board of Directors, Palo Alto Institute for Research and Education (PAVIR) (2014 - Present)
  • Member, Association of University Anesthesiologists (2006 - Present)
  • Member, American Pain Society (1998 - Present)
  • Member, International Association for the Study of Pain (1995 - Present)
  • Member, International Anesthesia Research Society (1993 - Present)
  • Member, American Society of Anesthesiologists (1993 - Present)

Professional Education

  • Board Certification, ABA, Pain Management (1998)
  • Board Certification, ABA, Anesthesiology (1996)
  • MD, Vanderbilt University, Medicine (1992)
  • PhD, Vanderbilt University, Pharmacology (1991)
  • BA, Carleton College, Chemistry (1985)


2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zou, Y., Corniola, R., Leu, D., Khan, A., Sahbaie, P., Chakraborti, A., Clark, D. J., Fike, J. R., Huang, T. 2012; 109 (52): 21522-21527


    Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampal-related functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that high-level EC-SOD may provide protection against irradiation-related defects in hippocampal functions.

    View details for DOI 10.1073/pnas.1216913110

    View details for Web of Science ID 000313627700077

    View details for PubMedID 23236175

    View details for PubMedCentralID PMC3535634

  • Modulation of remifentanil-induced postinfusion hyperalgesia by the beta-blocker propranolol in humans PAIN Chu, L. F., Cun, T., Ngai, L. K., Kim, J. E., Zamora, A. K., Young, C. A., Angst, M. S., Clark, D. J. 2012; 153 (5): 974-981


    Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.

    View details for DOI 10.1016/j.pain.2012.01.014

    View details for Web of Science ID 000302996200010

    View details for PubMedID 22365565

  • Collecting and measuring wound exudate biochemical mediators in surgical wounds. Journal of visualized experiments : JoVE Carvalho, B., Clark, D. J., Yeomans, D., Angst, M. S. 2012


    We describe a methodology by which we are able to collect and measure biochemical inflammatory and nociceptive mediators at the surgical wound site. Collecting site-specific biochemical markers is important to understand the relationship between levels in serum and surgical wound, determine any associations between mediator release, pain, analgesic use and other outcomes of interest, and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry. This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. We have measured wound exudate and serum mediators at the same time intervals as patient's pain scores and analgesics consumption for up to 48 hours post-cesarean delivery. Using this methodology we have been able to detect various biochemical mediators including nerve growth factor (NGF), prostaglandin E2 (PG-E2) substance P, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF, MCP-1 and MIP-1β. Studies applying this human surgical wound bioassay have found no correlations between wound and serum cytokine concentrations or their time-release profile (J Pain. 2008; 9(7):650-7).(1) We also documented the utility of the technique to identify drug-mediated changes in wound cytokine content.

    View details for DOI 10.3791/50133

    View details for PubMedID 23117346

  • Continuous Subcutaneous Instillation of Bupivacaine Compared to Saline Reduces Interleukin 10 and Increases Substance P in Surgical Wounds After Cesarean Delivery ANESTHESIA AND ANALGESIA Carvalho, B., Clark, D. J., Yeomans, D. C., Angst, M. S. 2010; 111 (6): 1452-1459


    Recent evidence suggests that locally delivered local anesthetics may exert tissue-damaging effects such as chondrolysis after intraarticular injection. Alteration of the inflammatory response is a potential mechanism for local anesthetic-induced tissue toxicity. In this study, we tested the effects of continuous local anesthetic infiltration on the release of inflammatory and nociceptive mediators in skin wounds after cesarean delivery.Thirty-eight healthy women undergoing cesarean delivery with spinal anesthesia were enrolled in this study, and were randomized to receive subcutaneous surgical wound infiltration with bupivacaine 5 mg/mL or saline at 2 mL/h for 24 hours after cesarean delivery. Wound exudate was sampled at 1, 3, 5, 7, and 24 hours after cesarean delivery using a subcutaneous wound drain technique. Cytokines, chemokines, substance P, prostaglandin E(2), and nerve growth factor were assayed using multiplex Bio-Plex® (Bio-Rad, Hercules, CA) and enzyme-linked immunosorbent assays.Bupivacaine wound infusion resulted in a significant decrease of interleukin 10 and increase of substance P in wounds compared with saline infusion (area under the 24-hour concentration-time curve; P < 0.001). No statistically significant differences were detected for other cytokines, nerve growth factor, and prostaglandin E(2).This study demonstrates that the continuous administration of clinically used doses of bupivacaine into wounds affects the local composition of wound mediators. Observed changes in interleukin 10 are compatible with a disruption of antiinflammatory mechanisms. Whether such modulation combined with the release of the proinflammatory mediator substance P results in an overall proinflammatory wound response will require future studies of wound healing.

    View details for DOI 10.1213/ANE.0b013e3181f579de

    View details for Web of Science ID 000284973300020

    View details for PubMedID 20861424

  • Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappa B activation, osteoclastogenesis and bone resorption BONE Wang, L., Shi, X., Zhao, R., Halloran, B. P., Clark, D. J., Jacobs, C. R., Kingery, W. S. 2010; 46 (5): 1369-1379


    Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin-gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP(+)) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-kappaB (NF-kappaB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10(-10)-10(-8) M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10(-8) M) inhibited receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP(+) cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-kappaB activation, osteoclastogenesis, and bone resorption.

    View details for DOI 10.1016/j.bone.2009.11.029

    View details for Web of Science ID 000276941000021

    View details for PubMedID 19962460

  • Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain IMPLEMENTATION SCIENCE Trafton, J. A., Martins, S. B., Michel, M. C., Wang, D., Tu, S. W., Clark, D. J., Elliott, J., Vucic, B., Balt, S., Clark, M. E., Sintek, C. D., Rosenberg, J., Daniels, D., Goldstein, M. K. 2010; 5


    Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients.Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools.The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools.Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.

    View details for DOI 10.1186/1748-5908-5-26

    View details for Web of Science ID 000277618600001

    View details for PubMedID 20385018

    View details for PubMedCentralID PMC2868045

  • Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro BONE Wang, L., Zhao, R., Shi, X., Wei, T., Halloran, B. P., Clark, D. J., Jacobs, C. R., Kingery, W. S. 2009; 45 (2): 309-320


    SP is a neuropeptide distributed in the sensory nerve fibers that innervate the medullar tissues of bone, as well as the periosteum. Previously we demonstrated that inhibition of neuropeptide signaling after capsaicin treatment resulted in a loss of bone mass and we hypothesized that SP contributes to bone integrity by stimulating osteogenesis.Osteoblast precursors (bone marrow stromal cells, BMSCs) and osteoclast precursors (bone marrow macrophages, BMMs) derived from C57BL/6 mice were cultured. Expression of the SP receptor (NK1) was detected by using immunocytochemical staining and PCR. Effects of SP on proliferation and differentiation of BMSCs were studied by measuring BrdU incorporation, gene expression, alkaline phosphatase activity, and osteocalcin and Runx2 protein levels with EIA and western blot assays, respectively. Effects of SP on BMMs were determined using a BrdU assay, counting multinucleated cells staining positive for tartrate-resistant acid phosphatase (TRAP(+)), measuring pit erosion area, and evaluating RANKL protein production and NF-kappaB activity with ELISA and western blot.The NK1 receptor was expressed in both BMSCs and BMMs. SP stimulated the proliferation of BMSCs in a concentration-dependent manner. Low concentrations (10(-12) M) of SP stimulated alkaline phosphatase and osteocalcin expression, increased alkaline phosphatase activity, and up-regulated Runx2 protein levels, and higher concentrations of SP (10(-8) M) enhanced mineralization in differentiated BMSCs. SP also stimulated BMSCs to produce RANKL, but at concentrations too low to evoke osteoclastogenesis in co-culture with macrophages in the presence of SP. SP also activated NF-kappaB in BMMs and directly facilitate RANKL-induced macrophage osteoclastogenesis and bone resorption activity.NK1 receptors are expressed by osteoblast and osteoclast precursors and SP stimulates osteoblast and osteoclast differentiation and function in vitro. SP neurotransmitter release from sensory neurons could potentially regulate local bone turnover in vivo.

    View details for DOI 10.1016/j.bone.2009.04.203

    View details for Web of Science ID 000268206300023

    View details for PubMedID 19379851

  • Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome EUROPEAN JOURNAL OF PAIN Wei, T., Sabsovich, I., Guo, T., Shi, X., Zhao, R., Li, W., Geis, C., Sommer, C., Kingery, W. S., Clark, D. J. 2009; 13 (3): 253-262


    Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia, a syndrome resembling complex regional pain syndrome (CRPS). Previous studies suggest that the pathogenesis of some of these changes involves an exaggerated regional inflammatory response to injury and we postulated that inflammatory cytokines contribute to the development of CRPS-like changes after fracture.The distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were given drinking water with or without the cytokine inhibitor pentoxifylline (PTX) starting the day before fracture and continuing for 4 weeks, after which time the cast was removed and multiple assays were performed in the hindpaw. PCR and immunoassays were used to evaluate changes in cytokine expression. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured by microcomputed tomography (microCT).Tibia fracture chronically up-regulated TNFalpha, IL-1beta and IL-6 mRNA and protein levels in hindpaw skin and PTX treatment significantly reduced the mRNA expression and cytokine protein levels for all these cytokines. PTX inhibited the nociceptive sensitization and some vascular changes, but had insignificant effects on most of the bone-related parameters measured in these studies. Immunostaining of hindpaw skin was negative for immunocyte infiltration at 4 weeks post-fracture.These results suggest that pro-inflammatory cytokines contribute to the nociceptive and vascular sequelae of fracture and that PTX treatment can reverse these CRPS-like changes.

    View details for DOI 10.1016/j.ejpain.2008.04.014

    View details for Web of Science ID 000264243300005

    View details for PubMedID 18554967

  • TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I PAIN Sabsovich, I., Guo, T., Wei, T., Zhao, R., Li, X., Clark, D. J., Geis, C., Sommer, C., Kingery, W. S. 2008; 137 (3): 507-519


    Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4 weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.

    View details for DOI 10.1016/j.pain.2007.10.013

    View details for Web of Science ID 000258359500009

    View details for PubMedID 18035493

  • Opioid-induced hyperalgesia in humans - Molecular mechanisms and clinical considerations CLINICAL JOURNAL OF PAIN Chu, L. F., Angst, M. S., Clark, D. 2008; 24 (6): 479-496


    Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.

    View details for Web of Science ID 000257198800003

    View details for PubMedID 18574358

  • Local and systemic release of cytokines, nerve growth factor, prostaglandin E2, and substance P in incisional wounds and serum following cesarean delivery JOURNAL OF PAIN Carvalho, B., Clark, D. J., Angst, M. S. 2008; 9 (7): 650-657


    The objectives of this study were to test the feasibility of measuring inflammatory and nociceptive biochemical mediators at the surgical site and to evaluate the relationship between wound and serum levels as well as determine any associations between mediator release, pain, and analgesic consumption after cesarean delivery. Twenty healthy women undergoing elective cesarean delivery with spinal anesthesia were enrolled. Wound exudate and serum mediators, pain scores, and analgesic consumption were measured at 1, 6, 24, and 48 hours after cesarean. In wound exudate, 19 of 20 mediators were reliably detected including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor-alpha, interferon-gamma, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1beta), nerve growth factor (NGF), prostaglandin E2 (PG-E2), and substance P. Wound PG-E2 and various cytokines peaked early, whereas NGF showed a more delayed release. There were no correlations between the concentration versus time profile of wound and serum cytokines. Analgesic consumption during the first 24 hours after surgery was negatively correlated with IL-1beta, IL-6, and G-CSF in the wound exudate. This study demonstrates the feasibility of collecting and measuring nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between wound and serum levels emphasizes the importance of determining site-specific release if localized pathologies are to be studied.This study demonstrates the feasibility of measuring real-time nociceptive and inflammatory mediators in surgical wounds. Our findings confirm the lack of correlation between wound and serum levels of many pro-inflammatory and anti-inflammatory cytokines and nerve growth factor.

    View details for DOI 10.1016/j.jpain.2008.02.004

    View details for Web of Science ID 000257640100010

    View details for PubMedID 18394968

  • Collecting and measuring nociceptive and inflammatory mediators in surgical wounds. Journal of visualized experiments : JoVE Carvalho, B., Clark, D. J., Yeomans, D., Angst, M. S. 2008


    We describe a methodology by which we are able to collect and measure inflammatory and nociceptive biochemical mediators at the surgical wound site. Collecting site-specific biochemical markers allows us to evaluate the relationship between surgical wound and serum levels;determine any associations between mediator release, pain and analgesic consumption; and evaluate the effect of systemic and peripheral drug administration on surgical wound biochemistry.This methodology has been applied to healthy women undergoing elective cesarean delivery with spinal anesthesia. Wound exudate and serum mediators, in conjunction with pain scores and analgesics consumption were measured at 1, 6, 24, and 48 hours post-cesarean delivery.Biochemical mediators that were detected included IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF,MCP-1 and MIP-1β, nerve growth factor (NGF), prostaglandin E2 (PG-E2) and substance P. We found no correlations between wound and serum cytokines concentrations or time-release profiles (J Pain. 2008 Jul 9(7):650-7). This article describes and demonstrates the feasibility of collecting and assaying nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between serum and wound levels shows the importance of determining site-specific release if surgical wounds and localized pathologies are to be studied [corrected].

    View details for DOI 10.3791/962

    View details for PubMedID 19078937

  • Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence PHARMACOGENETICS AND GENOMICS Liang, D., Liao, G., Lighthall, G. K., Peltz, G., Clark, D. J. 2006; 16 (11): 825-835


    Opioid-induced hyperalgesia (OIH) is a state of paradoxically increased nociceptive sensitivity seen in both humans and rodents following the resolution of the acute opioid antinociceptive effects or during periods of chronic opioid administration. Using the power of genetic analysis, we hoped to discover novel mechanisms modulating this trait.The degree of opioid-induced hyperalgesia displayed in response to a thermal stimulus applied to the hind paw was measured in 16 strains of inbred mice after 4 days of morphine administration. The degree of thermal sensitization was then used in a recently developed in silico haplotypic mapping algorithm along with a haplotypic map constructed from a database containing 209,000 single nucleotide polymorphisms.Analysis of the data resulted in the identification of several haplotype blocks strongly associated with the thermal opioid-induced hyperalgesia trait. The most strongly associated block was located within the Abcb1b P-glycoprotein drug transporter gene. Experiments using the P-glycoprotein inhibitor cyclosporine A and P-glycoprotein null mutant mice supported the hypothesis that a functional association exists between P-glycoprotein transporters and opioid-induced hyperalgesia. The observation of a correlation between morphine brain concentrations and the development of opioid-induced hyperalgesia was consistent with this hypothesis as well. In addition, P-glycoprotein gene deletion and pharmacological inhibition altered morphine ED50, tolerance and physical dependence.We conclude that the use of haplotypic mapping to identify novel mechanisms controlling complex traits is a viable approach. Variants of the Abcb1b gene may explain some portion of the interstrain differences in OIH and perhaps other consequences of chronic opioid administration.

    View details for Web of Science ID 000241971500008

    View details for PubMedID 17047491

  • Characteristics and treatment of headache after traumatic brain injury - A focused review AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION Lew, H. L., Lin, P., Fuh, J., Wang, S., Clark, D. J., Walker, W. C. 2006; 85 (7): 619-627


    Headache is one of the most common complaints in patients with traumatic brain injury. By definition, headache that develops within 1 wk after head trauma (or within 1 wk after regaining consciousness) is referred to as posttraumatic headache (PTH). Although most PTH resolves within 6-12 mos after injury, approximately 18-33% of PTH persists beyond 1 yr. We performed a systematic literature review on this topic and found that many patients with PTH had clinical presentations very similar to tension-type headache (37% of all PTH) and migraine (29% of all PTH). Although there is no universally accepted protocol for treating PTH, many clinicians treat PTH as if they were managing primary headache. As a result of the heterogeneity in the terminology and paucity in prospective, well-controlled studies in this field, there is a definite need for conducting double-blind, placebo-controlled treatment trials in patients with PTH.

    View details for DOI 10.1097/01.phm.0000223235.09931.c0

    View details for Web of Science ID 000238725500010

    View details for PubMedID 16788394

  • Persistence of rock-derived nutrients in the wet tropical forests of La Selva, Costa Rica ECOLOGY Porder, S., Clark, D. A., Vitousek, P. M. 2006; 87 (3): 594-602


    We used strontium isotopes and analysis of foliar and soil nutrients to test whether erosion can rejuvenate the supply of rock-derived nutrients in the lowland tropical rain forest of La Selva, Costa Rica. We expected that these nutrients would be depleted from soils on stable surfaces, a result of over one million years of weathering in situ. In fact, trees and palms in all landscape positions derive a relatively high percentage (> or =40%) of their strontium from bedrock, rather than atmospheric, sources. The fraction that is rock-derived increases on slopes, but with no detectable effect on plant macronutrient concentrations. These results differ from those in a similar ecosystem on Kauai, Hawaii, where plants on uneroded surfaces derive almost all of their foliar Sr from atmospheric, rather than bedrock, sources. The results from La Selva challenge the assumption that tropical Oxisols in general have low nutrient inputs from bedrock, and support the hypothesis that erosion can increase the supply of these nutrients in lower landscape positions.

    View details for Web of Science ID 000236289600008

    View details for PubMedID 16602289

  • Latent plaque rupture in a patient undergoing stenting for acute coronary syndrome and diffuse coronary disease: A case report and review of literature CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Koizumi, T., Wilson, A. M., Clark, D. A., Fitzgerald, P. J. 2006; 67 (2): 241-245


    Secondary prevention of plaque rupture following percutaneous coronary intervention in patients with acute coronary syndrome is not well studied. This case report describes a 53-year-old man who experienced plaque rupture between two previously successfully implanted stents in the right coronary artery, as documented during the 3rd intervention using intravascular ultrasound.

    View details for DOI 10.1002/ccd.20596

    View details for Web of Science ID 000235145100011

    View details for PubMedID 16400671

  • Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study JOURNAL OF PAIN Chu, L. F., Clark, D. J., Angst, M. S. 2006; 7 (1): 43-48


    There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients.Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.

    View details for DOI 10.1016/j.jpain.2005.08.001

    View details for Web of Science ID 000235142300008

    View details for PubMedID 16414554

  • Transient disruption of ventrolateral prefrontal cortex during verbal encoding affects subsequent memory performance JOURNAL OF NEUROPHYSIOLOGY Kahn, I., Pascual-Leone, A., Theoret, H., Fregni, F., Clark, D., Wagner, A. D. 2005; 94 (1): 688-698


    Episodic memory supports conscious remembrance of everyday experience. Prior functional neuroimaging data indicate that episodic encoding during phonological task performance is correlated with activation in bilateral posterior ventrolateral prefrontal cortex (pVLPFC), although uncertainty remains regarding whether these prefrontal regions make necessary contributions to episodic memory formation. Using functional MRI data to guide application of single-pulse transcranial magnetic stimulation (spTMS), this study examined the necessity of left and right pVLPFC for episodic encoding (as expressed through subsequent memory performance). To assess the timing of critical computations, pVLPFC function was transiently disrupted at different poststimulus onset times while subjects made syllable decisions about visually presented familiar and unfamiliar words; subsequent memory for these stimuli was measured. Results revealed that left pVLPFC disruption during encoding of familiar words impaired subsequent memory, expressed as a decline in recognition confidence, with disruption being maximal at 380 ms after stimulus onset. In contrast, right pVLPFC disruption facilitated subsequent memory for familiar words, expressed as an increase in medium confidence recognition, with this facilitation being maximal at 380 ms. Finally, phonological (syllable) decision accuracy was facilitated by right pVLPFC disruption, with this effect being maximal at 340 ms, but was unaffected by left pVLPFC disruption. These findings suggest that left pVLPFC mechanisms onset between 300 and 400 ms during phonological processing of words, with these mechanisms appearing necessary for effective episodic encoding. In contrast, disruption of correlated mechanisms in right pVLPFC facilitates encoding, perhaps by inducing a functional shift in the mechanisms engaged during learning.

    View details for DOI 10.1152/jn.01335.2004

    View details for Web of Science ID 000230135500061

    View details for PubMedID 15758048

  • Orientation of bound ligands in mannose-binding proteins - Implications for multivalent ligand recognition JOURNAL OF BIOLOGICAL CHEMISTRY Ng, K. K., Kolatkar, A. R., Park-Snyder, S., Feinberg, H., Clark, D. A., Drickamer, K., Weis, W. I. 2002; 277 (18): 16088-16095


    Mannose-binding proteins (MBPs) are C-type animal lectins that recognize high mannose oligosaccharides on pathogenic cell surfaces. MBPs bind to their carbohydrate ligands by forming a series of Ca(2+) coordination and hydrogen bonds with two hydroxyl groups equivalent to the 3- and 4-OH of mannose. In this work, the determinants of the orientation of sugars bound to rat serum and liver MBPs (MBP-A and MBP-C) have been systematically investigated. The crystal structures of MBP-A soaked with monosaccharides and disaccharides and also the structure of the MBP-A trimer cross-linked by a high mannose asparaginyl oligosaccharide reveal that monosaccharides or alpha1-6-linked mannose bind to MBP-A in one orientation, whereas alpha1-2- or alpha1-3-linked mannose binds in an orientation rotated 180 degrees around a local symmetry axis relating the 3- and 4-OH groups. In contrast, a similar set of ligands all bind to MBP-C in a single orientation. The mutation of MBP-A His(189) to its MBP-C equivalent, valine, causes Man alpha 1-3Man to bind in a mixture of orientations. These data combined with modeling indicate that the residue at this position influences the orientation of bound ligands in MBP. We propose that the control of binding orientation can influence the recognition of multivalent ligands. A lateral association of trimers in the cross-linked crystals may reflect interactions within higher oligomers of MBP-A that are stabilized by multivalent ligands.

    View details for DOI 10.1074/jbc.M200493200

    View details for Web of Science ID 000175510400116

    View details for PubMedID 11850428

  • Flying pigs and other possibilities Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions Clark, D. A. 2000; 51 (1): 10

    View details for PubMedID 10973009



    The purpose of this study was to evaluate the hypothesis that the increase in lumen area induced by percutaneous transluminal coronary angioplasty is secondary to a change in lesion (segmental) distensibility.Despite the widespread use of coronary angioplasty, the precise mechanism (or mechanisms) of lumen area improvement remains poorly understood.Quantitative coronary angiography was used to measure the minimal (contrast agent filled) balloon diameters at 1 to 5 atm, inclusive, during the first and final balloon inflations in 24 lesions successfully treated with coronary angioplasty. To rule out possible confounding effects due to changes in balloon material distensibility during repeated inflations, five control balloons were studied ex vivo. In parallel, intravascular ultrasound imaging was utilized to compare the segmental distensibility (change in lumen area during the cardiac cycle) of eight disease-free and seven mildly diseased coronary segments and seven segments after successful balloon angioplasty.Minimal balloon diameters increased significantly between the first and final inflations (46%, 33%, 26%, 14% and 10% at 1, 2, 3, 4 and 5 atm, respectively, all p < 0.0001), demonstrating an increase in arterial distensibility after successful coronary angioplasty. No significant changes in balloon diameters were observed during sequential initial inflations at 1 and 2 atm (n = 5). Minimal increases in balloon diameters were observed during repeated balloon inflations in the ex vivo studies (4.9 +/- 1% [mean +/- SEM]). A distensibility index, derived from the intravascular ultrasound data, was not different between the balloon-dilated and the normal segments but was significantly lower in mildly diseased sites (14.7 +/- 2.2 vs. 12.9 +/- 1.2 vs. 6.9 +/- 1.9, respectively, p < 0.05) despite a smaller plaque area (7.3 +/- 1 vs. 11.3 +/- 1 mm2, proximal/nondilated vs. dilated segments, respectively, p < 0.05).Coronary distensibility is significantly impaired in atherosclerotically diseased coronary segments and increases significantly after balloon angioplasty. This increase in segmental coronary compliance after coronary angioplasty may create a larger lumen area by allowing the vessel to distend in response to normal intraarterial pressure.

    View details for Web of Science ID A1994PH37100008

    View details for PubMedID 8144766



    Performance anxiety in musicians may be severe enough to require intervention but has been the subject of relatively little clinical research. The authors' objectives were to describe the results of a comprehensive clinical and laboratory assessment and to perform a double-blind, placebo-controlled study comparing buspirone, cognitive-behavior therapy, and the combination of these treatments for performance anxiety.Ninety-four subjects were recruited by mass media announcements and were seen in a university-based outpatient psychiatric clinic. Assessments were 1) questionnaires for all 94 subjects, 2) diagnostic interview of 50 subjects, and 3) laboratory performance of 34 subjects. Treatment conditions were 1) 6 weeks of buspirone, 2) 6 weeks of placebo, 3) a five-session, group cognitive-behavior therapy program with buspirone, or 4) the cognitive-behavior therapy program with placebo. Treatment outcome measures included subjective anxiety ratings and heart rate measures during a laboratory performance, a questionnaire measure of performance confidence, and a blind rating of musical performance quality.All subjects fulfilled criteria for DSM-III-R social phobia. Of the 15 full-time professional musicians, ten had tried propranolol and three had stopped performing. Most of the subjects had substantial anxiety and heart rate increases during laboratory speech and musical performances. Cognitive-behavior therapy resulted in statistically significant reductions in subjective anxiety, improved quality of musical performance, and improved performance confidence. Buspirone was not an effective treatment.Cognitive-behavior therapy is a viable treatment approach for performance anxiety in musicians.

    View details for Web of Science ID A1991FJ31700006

    View details for PubMedID 2018160

  • SURREPTITIOUS DRUG-USE BY PATIENTS IN A PANIC DISORDER STUDY AMERICAN JOURNAL OF PSYCHIATRY Clark, D. B., Taylor, C. B., Roth, W. T., Hayward, C., Ehlers, A., MARGRAF, J., Agras, W. S. 1990; 147 (4): 507-509


    In a double-blind, placebo-controlled trial comparing alprazolam and imipramine for panic disorder, serum analysis revealed that a substantial proportion of the patients took explicitly prohibited anxiolytic medication. Excluding these patients changed the results.

    View details for Web of Science ID A1990CW81000023

    View details for PubMedID 1969248



    Seventy-nine patients with panic disorder were randomized to an 8-week double-blind treatment with alprazolam, imipramine, or placebo. Patients kept daily records of panic attacks, activity, anxiety, sleep, and medication use. Weekly measures of anxiety, depression, somatic symptoms, fears, avoidance, disability, and improvement were obtained. All patients underwent a symptom-limited exercise treadmill and other cardiovascular measures. By physician and patient global assessment, patients receiving alprazolam or imipramine were significantly better than patients on placebo. The alprazolam effects were apparent by week 1; the imipramine effects by week 4. All groups showed significant reductions in anxiety, depression, somatic measures, and panic attack frequency. At 8 weeks, patients in the alprazolam group reported significantly less fear than patients in the other two groups. Subjects in the imipramine group showed a significant increase in heart rate and blood pressure.

    View details for Web of Science ID A1990CX84900006

    View details for PubMedID 2187912



    Personality theorists have long predicted a relationship between personality traits and autonomic activation. In this study, 48 patients with panic disorder underwent personality assessment by questionnaire (Eysenck Personality Inventory: 48 patients) and by interview (Personality Disorders Examination: 35 patients). Ambulatory heart rate and activity were measured by the Vitalog method and were used as measures of activation and autonomic arousal. There was a significant positive correlation between histrionic traits and activity level and a significant negative correlation between sociability and heart rate. The findings are consistent with previous studies showing a negative relationship between sensation-seeking personality traits and cerebrospinal fluid levels of norepinephrine and a positive relationship between extroversion and cerebrospinal fluid levels of dopamine.

    View details for Web of Science ID A1988P894700008

    View details for PubMedID 3217468

  • Treadmill exercise test and ambulatory measures in panic attacks. American journal of cardiology Taylor, C. B., King, R., Ehlers, A., MARGRAF, J., Clark, D., Hayward, C., Roth, W. T., Agras, S. 1987; 60 (18): 48J-52J


    Treadmill exercise test performance and ambulatory heart rate and activity patterns of 40 patients with panic attacks were compared with 20 age-matched controls (control group 1) and 20 nonexercising controls (control group 2). All patients underwent a symptom-limited exercise stress test. Panic attack patients and control group 1 wore an ambulatory heart rate/activity monitor for up to 3 days. Panic patients had a significantly higher heart rate at 4 and 6 METS than either control group. The max METS were 11.2 +/- 2.3, 13.5 +/- 2.3 and 11.2 +/- 1.8 for the panic attack patients and control groups 1 and 2, respectively. One panic patient had ischemia on the treadmill at 12 METS. Panic patients had a significantly higher standing heart rate than controls. Furthermore, 11 of 39 panic patients had tachycardia on standing compared with 3 of 40 controls. Panic attack patients had higher wake and sleep heart rates than control group 1, but the differences were not significant. These results are consistent with autonomic dysfunction in panic patients but may also be due to differences in physical conditioning. The treadmill can be useful for reassuring patients and for identifying the rare patient with ischemia on exercise.

    View details for PubMedID 3425557