Barbara A. Coda

Manipulating presence influences the magnitude of virtual reality analgesia.

&NA; Excessive pain during medical procedures performed in unanesthetized patients is frequently reported, but can be reduced with virtual reality (VR) distraction. Increasing the persons illusion of going into the virtual world may increase how effectively VR distracts pain. Healthy volunteers aged 18–20 years participated in a double‐blind between‐groups design. Each subject received a brief baseline thermal pain stimulus, and the same stimulus again minutes later with either a Low Tech or a High Tech VR distraction. Each subject provided subjective 0–10 ratings of cognitive, sensory and affective components of pain, and rated their illusion of going inside the virtual world. Subjects in the High Tech VR group reported a stronger illusion of going into the virtual world (VR presence) than subjects in the Low Tech VR group, (4.2 vs. 2.5, respectively, P=0.009) and more pain reduction (reduction of worst pain is 3.1 for High Tech VR vs. 0.7 for Low Tech VR, P<0.001). Across groups, the amount of pain reduction was positively and significantly correlated with VR presence levels reported by subjects (r=0.48 for ‘worst pain’, P<0.005).

The illusion of presence in immersive virtual reality during an fMRI brain scan.

The essence of immersive virtual reality (VR) is the illusion it gives users that they are inside the computer-generated virtual environment. This unusually strong illusion is theorized to contribute to the successful pain reduction observed in burn patients who go into VR during woundcare (www.vrpain.com) and to successful VR exposure therapy for phobias and post-traumatic stress disorder (PTSD). The present study demonstrated for the first time that subjects could experience a strong illusion of presence during an fMRI despite the constraints of the fMRI magnet bore (i.e., immobilized head and loud ambient noise).

The Analgesic Effects of Opioids and Immersive Virtual Reality Distraction: Evidence from Subjective and Functional Brain Imaging Assessments

BACKGROUND:Immersive virtual reality (VR) is a novel form of distraction analgesia, yet its effects on pain-related brain activity when used adjunctively with opioid analgesics are unknown. We used subjective pain ratings and functional magnetic resonance imaging to measure pain and pain-related brain activity in subjects receiving opioid and/or VR distraction. METHODS:Healthy subjects (n = 9) received thermal pain stimulation and were exposed to four intervention conditions in a within-subjects design: (a) control (no analgesia), (b) opioid administration [hydromorphone (4 ng/mL target plasma level)], (c) immersive VR distraction, and (d) combined opioid + VR. Outcomes included subjective pain reports (0–10 labeled graphic rating scales) and blood oxygen level-dependent assessments of brain activity in five specific, pain-related regions of interest. RESULTS:Opioid alone significantly reduced subjective pain unpleasantness ratings (P < 0.05) and significantly reduced pain-related brain activity in the insula (P < 0.05) and thalmus (P < 0.05). VR alone significantly reduced both worst pain (P < 0.01) and pain unpleasantness (P < 0.01) and significantly reduced pain-related brain activity in the insula (P < 0.05), thalmus (P < 0.05), and SS2 (P < 0.05). Combined opioid + VR reduced pain reports more effectively than did opioid alone on all subjective pain measures (P < 0.01). Patterns of pain-related blood oxygen level-dependent activity were consistent with subjective analgesic reports. CONCLUSIONS:These subjective pain reports and objective functional magnetic resonance imaging results demonstrate converging evidence for the analgesic efficacy of opioid administration alone and VR distraction alone. Furthermore, patterns of pain-related brain activity support the significant subjective analgesic effects of VR distraction when used as an adjunct to opioid analgesia. These results provide preliminary data to support the clinical use of multimodal (e.g., combined pharmacologic and nonpharmacologic) analgesic techniques.

Hydromorphone analgesia after intravenous bolus administration

Abstract This study investigated the analgesic effects of three intravenous bolus doses of hydromorphone (10, 20, 40 &mgr;g/kg) on experimental pain measures in normal humans. Ten healthy male volunteers participated in four study sessions, one for each of the hydromorphone doses as well as a placebo (saline). They received the four treatments in counterbalanced order under double‐blind conditions and with study days at least 1 week apart. During each session subjects underwent repeated electrical tooth pulp stimulation at intensities sufficient to elicit a rating of ‘strong pain’ before drug administration. Subjective pain reports (PRs) and dental evoked potential amplitude measures (EPs) served as analgesic effect indicators. We observed dose‐dependent analgesia as measured by both PR (P=0.009) and EP (P=0.017). Area under the PR versus time curve as well as the EP versus time curve decreased in a log dose‐dependent fashion. Although the peak effect was poorly defined, the onset of analgesia was rapid, within 5 min, and maximum analgesic effect was seen between 10 and 20 min after maximum plasma hydromorphone concentration. However, within sessions we found a poor correspondence between hydromorphone plasma concentration and effect. Compared to pain report data from other human studies done in our laboratory, hydromorphone has a shorter time to peak effect compared to morphine, and overall, hydromorphone hydrochloride is approximately five times as potent as morphine sulfate on a milligram basis.

MULTIPLE-DOSE EVALUATION OF INTRAVENOUS HYDROMORPHONE PHARMACOKINETICS IN NORMAL HUMAN SUBJECTS

We measured the pharmacokinetics of hydromorphone in normal volunteers given three doses of the drug (10, 20, and 40 μg/kg) as intravenous 45-s injections on different days. Concentrations of hydromorphone in plasma from serial blood samples were measured by a high‐performance liquid chromatography method specific for hydromorphone with a detection limit of 0.1 ng/mL. In all cases, plasma hydromorphone concentration versus time data for individual subjects were best described by a triexponential (instead of mono- or biexponential) function. Furthermore, we found that the pharmacokinetics of hydromorphone was independent of dose across the range studied. Averaged across doses, the distribution and terminal elimination half‐lives were 1.27 min (t1/2π), 14.7 min (t1/2α), and 184 min (t1/2β), respectively. Average values for systemic clearance, initial dilution volume, and steady‐state volume of distribution were 1.66 L/min (Cl), 24.4 L (Vc), and 295 L (Vdss). Our results indicate that hydromorphone pharmacokinetic parameters are linear across a fourfold range of doses that are usually employed clinically and that previously reported pharmacokinetic values for hydromorphone (based on radioimmunoassay measurements) deserve reconsideration.

Patient-controlled analgesic administration. A comparison of steady-state morphine infusions with bolus doses.

The authors have shown previously that bone marrow transplant (BMT) patients who self‐administered bolus doses of morphine gained equal oral mucositis pain relief while using less drug compared with similar patients receiving morphine by staff‐controlled continuous infusion. In a follow‐up study they compared the efficacy and side effects of morphine in two groups of marrow transplant patients who controlled their own analgesic administration either by conventional bolusdose, patient‐controlled analgesia (PCA) or by adjusting the rate of continuous morphine infusion to increase or decrease their plasma morphine concentration. Patients controlling their morphine infusion rates (pharmacokinetically based patient‐controlled analgesia [PKPCA] group) obtained more relief from oral mucositis pain than did patients using conventional PCA. Patients in the PKPCA group used more morphine than PCA patients and achieved superior pain relief without significant increases in side effects (e.g., nausea, mood changes, sedation). The authors conclude that PKPCA improves the management of prolonged, severe pain in marrow transplant patients and that this approach to patient‐controlled analgesia may be useful in other types of persistent pain.

Patient-controlled analgesic infusions: alfentanil versus morphine

&NA; Previously, we found that cancer patients using a pharmacokinetically based patient‐controlled intravenous infusion system (PKPCA) to regulate their own morphine infusion rates achieved more relief from oral mucositis pain than similar patients using morphine by bolus‐dose PCA. In this study, we employed the PKPCA system to compare efficacy and side‐effect intensities of 2 mu‐selective opioid analgesics, alfentanil and morphine, in bone marrow transplant (BMT) patients self‐administering the drugs to relieve pain from oral mucositis. Patients using morphine by PKPCA obtained more pain relief than patients regulating their own alfentanil infusions during the first 4 days of continuous opioid infusion therapy. Side‐effect intensities did not differ between the 2 study groups. In contrast to patients using morphine for 4–14 days, those receiving alfentanil by PKPCA required unexpectedly high plasma concentrations of the drug to obtain equivalent pain relief. Our results indicate that either the relative potencies of these 2 mu‐selective opioids differ from previous estimates or analgesic tolerance developed to alfentanil but not to morphine. We conclude that alfentanil has similar efficacy in control of prolonged pain in BMT patients, but the utility of alfentanil in long‐term pain management may be limited by relatively rapid tolerance onset.

Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions

&NA; We evaluated the ability of fenfluramine, a serotonin releaser, to increase the analgesic potency of morphine administered by tailored i.v. infusion. Ten normal volunteers participated in 4 test sessions, involving different treatments on different days: (1) oral placebo/saline infusion, (2) oral placebo/morphine infusion, (3) oral fenfluramine (60 mg)/saline infusion, and (4) oral fenfluramine/morphine infusion. Subjects experienced repetitive painful dental electrical stimuli at strong but tolerable intensities during testing. On the 2 test days involving morphine, the opioid was administered by a computer‐pump system that used individual pharmacokinetic parameters to achieve consecutive, steady plasma concentrations near target values of 16, 32 and 64 ng morphine/ml; each morphine concentration plateau was maintained for 45 min. On the saline infusion days, our procedures were identical to morphine test days except that the infused fluid contained no drug. For all sessions outcome measures included subject ratings of pain intensity, dental evoked potential (EP) amplitude, and visual analog scale (VAS) ratings of subjective side‐effect intensities (nausea, alertness, dizziness, itching, mood). We obtained these measures during baseline and at each morphine concentration plateau or at corresponding times during saline infusions. Fenfluramine significantly increased the analgesic potency of morphine during the opioid infusion, while fenfluramine alone produced borderline analgesic effects. Fenfluramine alone decreased alertness slightly, but did not significantly increase morphine side effects. Thus, we conclude that fenfluramine enhances the analgesic potency of morphine without a parallel increase in opioid side‐effect potency.

Morphine-Fluoxetine Interactions in Healthy Volunteers: Analgesia and Side Effects

The authors evaluated the ability of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), to enhance the analgesic potency of morphine. Fifteen volunteers participated in this double‐blind crossover study. All received combinations of morphine or saline with either fluoxetine 30 mg or placebo. The authors used individual morphine pharmacokinetics to program an infusion pump to achieve plasma morphine levels of 15, 30, and 60 ng/ml. Analgesia during morphine infusion was assessed using a model of electrical tooth stimulation. Subjective side effects, measurements of end‐tidal CO2, O2 saturation, pupil size, and testing of psychomotor performance were obtained. Plasma morphine concentrations were not affected by fluoxetine. In comparison to placebo, oral fluoxetine resulted in less sedation during morphine infusion and less nausea during morphine washout. Morphine‐induced pruritus, psychomotor function, and respiratory depression were unaffected by fluoxetine. Acute administration of 30 mg oral fluoxetine augmented analgesia by approximately 3% to 8% and reduced morphine‐associated nausea, mood reduction, and drowsiness.

A computer-based system for controlling plasma opioid concentration according to patient need for analgesia

SummaryMicroprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.