Carroll I, Barelka P, Wang CKM, et al. A pilot cohort study of the determinants of longitudinal opioid use after surgery. Anesth. Analg. 2012;115(3):694-702.
BACKGROUND: Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery. METHODS: Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done. RESULTS: Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity. CONCLUSIONS: Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.
Chapin H, Bagarinao E, Mackey S. Real-time fMRI applied to pain management. Neurosci. Lett. 2012;520(2):174-181.
Current views recognize the brain as playing a pivotal role in the arising and maintenance of pain experience. Real-time fMRI (rtfMRI) feedback is a potential tool for pain modulation that directly targets the brain with the goal of restoring regulatory function. Though still relatively new, rtfMRI is a rapidly developing technology that has evolved in the last 15 years from simple proof of concept experiments to demonstrations of learned control of single and multiple brain areas. Numerous studies indicate rtfMRI feedback assisted control over specific brain areas may have applications including mood regulation, language processing, neurorehabilitation in stroke, enhancement of perception and learning, and pain management. We discuss in detail earlier work from our lab in which rtfMRI feedback was used to train both healthy controls and chronic pain patients to modulate anterior cingulate cortex (ACC) activation for the purposes of altering pain experience. Both groups improved in their ability to control ACC activation and modulate their pain with rtfMRI feedback training. Furthermore, the degree to which participants were able to modulate their pain correlated with the degree of control over ACC activation. We additionally review current advances in rtfMRI feedback, such as real-time pattern classification, that bring the technology closer to more comprehensive control over neural function. Finally, remaining methodological questions concerning the further development of rtfMRI feedback and its implications for the future of pain research are also discussed.


Mogil JS, Rice FL, Brennan TJ, et al. Secure Sign In. Curr. Pharm. Biotechnol. 2011.
Sam WJ, Mackey SC, Lötsch J, Drover DR. Morphine and its metabolites after patient-controlled analgesia: considerations for respiratory depression. J. Clin. Anesth. 2011;23(2):102-106.
STUDY OBJECTIVE: To assess concentrations of morphine and its metabolites after patient-controlled analgesia (PCA). DESIGN: Pilot pharmacokinetic study of morphine and pharmacokinetic simulation. SETTING: Post-anesthesia care room and ward of an academic teaching hospital. PATIENTS: 10 ASA physical status I, II, and III postoperative surgical patients. INTERVENTIONS: Patients received morphine via PCA by routine hospital protocols. MEASUREMENTS: The population mean plasma and effect-site concentrations of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) was simulated in 4 patient group scenarios: morphine PCA used alone, morphine PCA used with continuous background morphine infusion of 0.5 mg/hr, morphine PCA used with continuous background morphine infusion of 1.0 mg/hr, and morphine PCA used with continuous background morphine infusion of 2.0 mg/hr. MAIN RESULTS: The 4 groups exhibited simulated peak morphine, M6G, and M3G effect-site concentrations at 8 to 24 hours post-infusion. The highest peak morphine, M6G, and M3G effect-site concentrations decreased in the following order by group: 2.0 mg/hr morphine infusion + PCA group, 1.0 mg/hr morphine infusion + PCA group, and 0.5. mg/hr morphine infusion + PCA group. CONCLUSIONS: Patients receiving morphine PCA should be monitored closely from 8 to 24 hours postoperatively. Morphine PCA given with background infusion rates up to 1.0 mg/hr does not offer distinct pharmacokinetic advantages over morphine PCA alone. Morphine PCA with background infusion rate of 2.0 mg/hr is associated with the greatest risk of respiratory depression.
Younger JW, Chu LF, Arcy NTD, Trott KE, Jastrzab LE, Mackey SC. Prescription opioid analgesics rapidly change the human brain. Pain. 2011;152(8):1803-1810.
Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.
Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p\textless0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings.
Carroll I, Fischbein N, Barad M, Mackey S. Human response to unintended intrathecal injection of botulinum toxin. Pain Med. 2011;12(7):1094-1097.
OBJECTIVE: Describe the first reported human intrathecal (IT) botulinum toxin injection. DESIGN: Case report. SETTING AND PATIENTS: We report here the sequelae to an unintended IT injection of botulinum toxin type B (BTB) in a 60-year-old woman with chronic back pain. RESULTS: Following the IT administration of BTB, the patient experienced the onset of symmetric ascending stocking distribution painful dysesthesias, which persisted for approximately 6 months before receding. Objective neurologic deficits were not appreciated, and analgesic effects were prominently absent. CONCLUSIONS: Analgesic actions of botulinum toxins in animals and in humans have led to speculation that IT botulinum toxin might exert significant analgesic effects. The unusual and unexpected subsequent clinical course, neurologic sequelae, dysesthesias, and absence of analgesia suggest that botulinum toxin will not be a therapeutic modality to treat pain as proposed by those studying botulinum toxin in animal models.


Parris D, Fischbein N, Mackey S, Carroll I. A novel CT-guided transpsoas approach to diagnostic genitofemoral nerve block and ablation. Pain Med. 2010;11(5):785-789.
BACKGROUND: Inguinal hernia repair is associated with a high incidence of chronic postsurgical pain. This pain may be caused by injury to the iliohypogastric, ilioinguinal, or genitofemoral nerves. It is often difficult to identify the specific source of the pain, in part, because these nerves are derived from overlapping nerve roots and closely colocalize in the area of surgery. It is therefore technically difficult to selectively block these nerves individually proximal to the site of surgical injury. In particular, the genitofemoral nerve is retroperitoneal before entering the inguinal canal, a position that puts anterior approaches to the proximal nerve at risk of transgressing into the peritoneum. We report a computed tomography (CT)-guided transpsoas technique to selectively block the genitofemoral nerve for both diagnostic and therapeutic purposes while avoiding injury to the nearby ureter and intestines. CASE: A 39-year-old woman with chronic lancinating right groin pain after inguinal hernia repair underwent multiple pharmacologic interventions and invasive procedures without relief. Using CT and Stimuplex nerve stimulator guidance, the genitofemoral nerve was localized on the anterior surface of the psoas muscle and a diagnostic block with local anesthetic block was performed. The patient had immediate relief of her symptoms for 36 hours, confirming the diagnosis of genitofemoral neuralgia. She subsequently underwent CT-guided radiofrequency and phenol ablation of the genitofemoral nerve but has not achieved long-term analgesia. CONCLUSION: CT-guided transpsoas genitofemoral nerve block is a viable option for safely and selectively blocking the genitofemoral nerve for diagnostic or therapeutic purposes proximal to injury caused by inguinal surgery.