RESUMEN
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 thalamus (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), thalamus (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.
Asunto(s)
Analgésicos Opioides/farmacología , Emociones , Imagen por Resonancia Magnética/métodos , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Interfaz Usuario-Computador , Adulto , Mapeo Encefálico/métodos , Simulación por Computador , Emociones/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética/psicología , Masculino , Dimensión del Dolor/psicologíaRESUMEN
We evaluated the pharmacokinetics, tolerability, and safety of 1 and 2 mg of intranasal hydromorphone hydrochloride in an open-label, single- and multiple-dose study. This Phase I study was conducted in 24 healthy volunteers (13 men and 11 women). Intranasal doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1- and 2-mg doses, respectively. Venous blood samples were taken serially from 0 to 12 h after the first single dose and the last (seventh) multiple dose. Plasma hydromorphone concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic variables. After 7 intranasal doses of 1 and 2 mg (once every 6 h), mean +/- sd peak plasma concentrations of 2.8 +/- 0.7 ng/mL and 5.3 +/- 2.3 ng/mL, respectively, were observed. The median time to peak concentration was 20 min for both single and multiple doses. Dose proportionality was observed for the 1- and 2-mg doses. Adverse events included somnolence, dizziness, and bad taste after dose administration. Intranasal hydromorphone hydrochloride was well tolerated and demonstrated rapid nasal drug absorption and predictable accumulation. These results support clinical investigation of hydromorphone hydrochloride nasal spray for use as an alternative to oral and IM administration.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Hidromorfona/administración & dosificación , Hidromorfona/farmacocinética , Absorción , Administración Intranasal , Adolescente , Adulto , Analgésicos Opioides/efectos adversos , Área Bajo la Curva , Química Farmacéutica , Cromatografía Liquida , Método Doble Ciego , Femenino , Semivida , Humanos , Hidromorfona/efectos adversos , Masculino , Espectrometría de Masas , Inhaladores de Dosis MedidaRESUMEN
UNLABELLED: We evaluated pharmacokinetics and absolute bioavailability of single doses of hydromorphone hydrochloride after administration of 1.0 and 2.0 mg of intranasal (IN) and 2.0 mg of IV hydromorphone hydrochloride. An open-label, randomized, three-way crossover study was conducted in 24 healthy volunteers (13 men and 11 women). IN doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1.0- and 2.0-mg doses, respectively. Blood samples were taken serially from 0 to 16 h after each dose. Plasma hydromorphone concentrations were determined by liquid chromatography-mass spectrometry-mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic variables. Mean hydromorphone bioavailabilities and percent coefficient of variation of 52.4% (22.7) and 57.5% (18.6) were seen after the 1.0- and 2.0-mg IN doses, respectively. Median times to maximum concentration were 20 and 25 min for IN doses. Adverse events included somnolence and dizziness with all routes of administration and a bad taste after IN doses. Dose proportionality for the 1.0- and 2.0-mg IN doses was observed. IN hydromorphone hydrochloride met the minimum requirements for safety and demonstrated rapid nasal drug absorption and clinically relevant bioavailability. Results support further development of this novel hydromorphone hydrochloride nasal spray. IMPLICATIONS: Pharmacokinetics and bioavailability were determined for two doses of intranasal hydromorphone in healthy volunteers. Rapid, reliable absorption, and predictable pharmacokinetics support the investigation of hydromorphone hydrochloride nasal spray as a therapeutic alternative to oral and IM administration.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Hidromorfona/administración & dosificación , Hidromorfona/farmacocinética , Administración Intranasal , Adolescente , Adulto , Analgésicos Opioides/efectos adversos , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidromorfona/efectos adversos , Inyecciones Intravenosas , Masculino , Mucosa Nasal/patologíaRESUMEN
A pilot study was conducted in 7 normal volunteers to demonstrate the feasibility of employing pharmacokinetic tailoring to achieve matching plasma opioid concentration-time curves after epidural (e.p.) and intravenous (i.v.) alfentanil administration. Each subject participated in 1 pretest and 2 test sessions. Our pain model was cutaneous electrical stimulation of the finger and toe, adjusted to produce a baseline pain report of 5 (strong pain on a 0-5 scale). On test day 1, subjects received e.p. alfentanil (750 micrograms) and an i.v. saline infusion. Serial measurements of analgesia, end tidal CO2, pupil size, subjective side effects, and plasma alfentanil concentrations were conducted before and at various time intervals over a 4-h period after alfentanil administration. On test day 2, subjects received e.p. saline and a pharmacokinetically tailored i.v. infusion (using individual pharmacokinetics determined on the pretest day) designed to achieve a plasma concentration-time profile identical to that observed on the epidural day. The same battery of effect measurements was administered as on the 1st test day. Plasma alfentanil was measured to verify the accuracy of the tailored infusion. Plasma alfentanil concentration profiles were nearly identical on both test days. Peak plasma alfentanil concentrations were near the reported minimum effective analgesic concentration (MEAC). Overall, analgesia was slightly greater with e.p. administration. Onset of pain relief was rapid, and duration was approximately 1.5 h with e.p. and 1 h with i.v. alfentanil. There were no differences in pupil size, ETCO2, or subjective side effects between e.p. versus i.v. administration. We conclude that systemic redistribution from the epidural space appears to account for most, but not all, of the analgesia.
Asunto(s)
Alfentanilo/administración & dosificación , Alfentanilo/sangre , Analgesia Epidural , Adulto , Alfentanilo/efectos adversos , Estudios Cruzados , Estudios de Factibilidad , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Análisis Multivariante , Concentración Osmolar , Proyectos Piloto , Método Simple CiegoRESUMEN
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.
Asunto(s)
Analgesia , Fenfluramina/farmacología , Morfina/farmacología , Adulto , Pulpa Dental/fisiología , Sinergismo Farmacológico , Estimulación Eléctrica , Fenfluramina/efectos adversos , Fenfluramina/farmacocinética , Humanos , Infusiones Intravenosas , Masculino , Morfina/efectos adversos , Morfina/farmacocinética , Dimensión del Dolor/efectos de los fármacosRESUMEN
The primary purpose of this study was to examine whether alprazolam pretreatment can increase the analgesic potency of morphine without increasing opioid side-effect intensities. We employed computer-controlled, variable-rate morphine infusions based on each subject's pharmacokinetic profile for morphine derived from a tailoring bolus dose of the drug administered 1 or 2 weeks before the infusion test sessions. On each of 2 test days, we used dental electrical stimulation to determine stimulus intensity that produced consistent reports of strong (but tolerable) pain; this intensity was used for the rest of that session. Then, we measured baseline (no drug) pain intensity reports, pain-related evoked potentials recorded from vertex, and other parameters typically affected by opioids (subjective side effects). We administered alprazolam (1 mg) or placebo (lactose) orally to the subject and then repeated the test battery 30 min later. One hour after the alprazolam or placebo dose, we initiated the tailored morphine infusion to reach target plasma morphine concentration plateaus of 16, 32 and 64 ng/ml (45-min duration each) on both test days. The test battery used during baseline was then repeated at each target concentration plateau. The order of alprazolam versus placebo pretreatments was counterbalanced across subjects and known only to the investigator operating the infusion system. Results suggest that alprazolam at the dose studied did not alter analgesic potency of morphine. However, alprazolam did clearly decrease the intensity of nausea reported by subjects during and after termination of the morphine infusions. Of special interest, alprazolam alone (30 min after oral dosing) decreased evoked potential amplitude consistently without affecting pain intensity reports.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Alprazolam/farmacología , Analgesia , Morfina/farmacología , Adulto , Alprazolam/sangre , Sinergismo Farmacológico , Homeostasis , Humanos , Infusiones Intravenosas , Masculino , Morfina/efectos adversos , Morfina/sangre , Proyectos Piloto , Autoevaluación (Psicología)RESUMEN
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.