Vishvarani Wanigasekera

The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil

An individual’s expectation that a pain treatment will or will not work can alter both its subjective effectiveness and the pain-related activity in the brain. Gloomy Forecasts Prove True A pessimist walks into a hospital. His grim prediction that doctors will be unable to alleviate his back pain proved correct—after several days of various treatments, his pain persisted. According to new results from Bingel and colleagues, the gloomy outlook this patient brought with him into his pain treatment may have ensured that his prediction was a self-fulfilling prophesy. Using sophisticated brain imaging techniques, the authors show that one’s expectation of the success of a pain treatment can markedly influence its effectiveness. In this new study, healthy people were exposed to pain-provoking heat and also given the painkilling opioid drug remifentanil. In advance of each instance of drug administration, the authors informed the subjects that the drug would have no effect, that it would diminish the sensation of pain, or that it would make the pain worse. When subjects expected the drug to be effective, they were not disappointed—they experienced twice as much pain relief as they did when they expected to obtain no benefit from the drug (but did, in fact, get some relief). In contrast, when they expected remifentanil to make the heat pain worse they found that their pain was unchanged. But these subjective reports could be influenced by a host of variables. What was actually happening within the brains of these individuals to shift their pain perceptions so dramatically? With functional magnetic resonance imaging (fMRI), the authors of Bingel et al. examined brain activity during the experiment. Thermal pain itself causes activation of a so-called pain circuit, which encompasses numerous brain regions including the somatosensory cortex, the cingulate cortex, insula, thalamus, and brainstem. Expectation of increased pain was accompanied by more neural activity in the hippocampus, midcingulate cortex, and medial prefrontal cortex—brain areas that mediate mood and anxiety—than was observed in these regions during expectation of analgesia. Conversely, individuals who expected the drug to mitigate their pain showed increases in the anterior cingulate cortex and the striatum, signs that descending mechanisms of pain inhibition were engaged. These clues about how our beliefs can affect the way we experience medical treatment for pain can improve the practice of medicine. A drug with a true biological effect may appear to be ineffective to a patient conditioned to expect failure, whether the patient is enrolled in a clinical trial or treated in a physician’s office. Patient education about treatments can help counteract this problem by shaping beliefs to maximize drug effectiveness. If appropriate treatments are accompanied by encouraging words, a pessimist could become an optimist about his future robust health, and thereby make it so. Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

Amygdala activity contributes to the dissociative effect of cannabis on pain perception.

Summary fMRI evidence suggests that delta‐9‐tetrahydrocannabinol, the psychoactive component of cannabis, targets the affective aspects of pain in humans by altering the activity and functional connections of the amygdala. Abstract Cannabis is reported to be remarkably effective for the relief of otherwise intractable pain. However, the bases for pain relief afforded by this psychotropic agent are debatable. Nonetheless, the frontal‐limbic distribution of cannabinoid receptors in the brain suggests that cannabis may target preferentially the affective qualities of pain. This central mechanism of action may be relevant to cannabinoid analgesia in humans, but has yet to be demonstrated. Here, we employed functional magnetic resonance imaging to investigate the effects of delta‐9‐tetrahydrocannabinol (THC), a naturally occurring cannabinoid, on brain activity related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin in healthy volunteers. On average, THC reduced the reported unpleasantness, but not the intensity of ongoing pain and hyperalgesia: the specific analgesic effect on hyperalgesia was substantiated by diminished activity in the anterior mid cingulate cortex. In individuals, the drug‐induced reduction in the unpleasantness of hyperalgesia was positively correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during the ongoing‐pain state. Critically, the reduction in sensory‐limbic functional connectivity was positively correlated with the difference in drug effects on the unpleasantness and the intensity of ongoing pain. Peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed. Instead, the data reveal that amygdala activity contributes to interindividual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans.

Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects.

Variability in opioid analgesia has been attributed to many factors. For example, genetic variability of the μ-opioid receptor (MOR)-encoding gene introduces variability in MOR function and endogenous opioid neurotransmission. Emerging evidence suggests that personality trait related to the experience of reward is linked to endogenous opioid neurotransmission. We hypothesized that opioid-induced behavioral analgesia would be predicted by the trait reward responsiveness (RWR) and the response of the brain reward circuitry to noxious stimuli at baseline before opioid administration. In healthy volunteers using functional magnetic resonance imaging and the μ-opioid agonist remifentanil, we found that the magnitude of behavioral opioid analgesia is positively correlated with the trait RWR and predicted by the neuronal response to painful noxious stimuli before infusion in key structures of the reward circuitry, such as the orbitofrontal cortex, nucleus accumbens, and the ventral tegmental area. These findings highlight the role of the brain reward circuitry in the expression of behavioral opioid analgesia. We also show a positive correlation between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in key structures of the descending pain modulatory system (amygdala, periaqueductal gray, and rostral–ventromedial medulla), as well as the hippocampus. Further, these activity changes were predicted by the preinfusion period neuronal response to noxious stimuli within the ventral tegmentum. These results support the notion of future imaging-based subject-stratification paradigms that can guide therapeutic decisions.

Learning to identify CNS drug action and efficacy using multistudy fMRI data

Existing functional brain imaging data sets were used to identify neural signatures that confirm pharmacological action and predict clinical efficacy of test compounds. Brain patterns determine drug efficacy There are many drugs out there that affect the central nervous system (CNS), from drugs for chronic pain to schizophrenia to obesity. A brain imaging technique called functional magnetic resonance imaging (fMRI) has shown promise for distinguishing an effective compound from an ineffective one, but the real unmet need is to be able to predict whether a new CNS drug will have clinical efficacy. To this end, Duff et al. evaluated existing fMRI data sets for patients who were exposed to painful stimuli (such as heat or a squeeze) and given either an analgesic compound or a placebo. From these brain “maps,” or neural signatures, the authors were able to create a general “stop/go” decision-making framework—which included quality assurance, pharmacodynamic effect, and evidence for clinical efficacy steps—that allowed them to determine whether the signature of a new compound provided evidence for analgesic properties. Other than evaluating potential drug efficacy, the authors revealed insights into pain response mechanisms. This multistudy approach by Duff et al. may translate to a powerful tool in synthesizing and learning from neuroimaging data to improve—and perhaps speed up—CNS drug discovery and repurposing. The therapeutic effects of centrally acting pharmaceuticals can manifest gradually and unreliably in patients, making the drug discovery process slow and expensive. Biological markers providing early evidence for clinical efficacy could help prioritize development of the more promising drug candidates. A potential source of such markers is functional magnetic resonance imaging (fMRI), a noninvasive imaging technique that can complement molecular imaging. fMRI has been used to characterize how drugs cause changes in brain activity. However, variation in study protocols and analysis techniques has made it difficult to identify consistent associations between subtle modulations of brain activity and clinical efficacy. We present and validate a general protocol for functional imaging–based assessment of drug activity in the central nervous system. The protocol uses machine learning methods and data from multiple published studies to identify reliable associations between drug-related activity modulations and drug efficacy, which can then be used to assess new data. A proof-of-concept version of this approach was developed and is shown here for analgesics (pain medication), and validated with eight separate studies of analgesic compounds. Our results show that the systematic integration of multistudy data permits the generalized inferences required for drug discovery. Multistudy integrative strategies of this type could help optimize the drug discovery and validation pipeline.

Stimulus Site and Modality Dependence of Functional Activity within the Human Spinal Cord

Chronic pain is thought to arise because of maladaptive changes occurring within the peripheral nervous system and CNS. The transition from acute to chronic pain is known to involve the spinal cord (Woolf and Salter, 2000). Therefore, to investigate altered human spinal cord function and translate results obtained from other species, a noninvasive neuroimaging technique is desirable. We have investigated the functional response in the cervical spinal cord of 18 healthy human subjects (aged 22–40 years) to noxious thermal and non-noxious tactile stimulation of the left and right forearms. Physiological noise, which is a significant source of signal variability in the spinal cord, was accounted for in the general linear model. Group analysis, performed using a mixed-effects model, revealed distinct regions of activity that were dependent on both the side and the type of stimulation. In particular, thermal stimulation on the medial aspect of the wrist produced activity within the C6/C5 segment ipsilateral to the side of stimulation. Similar to data recorded in animals (Fitzgerald, 1982), painful thermal stimuli produced increased ipsilateral and decreased contralateral blood flow, which may reflect, respectively, excitatory and inhibitory processes. Nonpainful punctate stimulation of the thenar eminence provoked more diffuse activity but was still ipsilateral to the side of stimulation. These results present the first noninvasive evidence for a lateralized response to noxious and non-noxious stimuli in the human spinal cord. The development of these techniques opens the path to understanding, at a subject-specific level, central sensitization processes that contribute to chronic pain states.

Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.

Preclinical evidence suggests that opioid withdrawal induces central sensitization (CS) that is maintained by supraspinal contributions from the descending pain modulatory system (DPMS). Here, in healthy human subjects we use functional magnetic resonance imaging to study the supraspinal activity during the withdrawal period of the opioid remifentanil. We used a crossover design and thermal stimuli on uninjured skin to demonstrate opioid withdrawal-induced hyperalgesia (OIH) without a CS-inducing peripheral stimulus. Saline was used in the control arm to account for effects of time. OIH in this injury-free model was observed in a subset of the healthy subjects (responders). Only in these subjects did opioid infusion and withdrawal induce a rise in activity in the mesencephalic-pontine reticular formation (MPRF), an area of the DPMS that has been previously shown to be involved in states of CS in humans, which became significant during the withdrawal phase compared with nonresponders. Paradoxically, this opioid withdrawal-induced rise in MPRF activity shows a significant negative correlation with the behavioral OIH score indicating a predominant inhibitory role of the MPRF in the responders. These data illustrate that in susceptible individuals central mechanisms appear to regulate the expression of OIH in humans in the absence of tissue injury, which might have relevance for functional pain syndromes where a peripheral origin for the pain is difficult to identify.

Graded myocardial ischemia is associated with a decrease in diastolic distensibility of the remote nonischemic myocardium in the anesthetized dog

OBJECTIVES This study was designed to investigate the changes in regional distensibility of the ischemic segment and of a remote nonischemic segment brought about by graded myocardial ischemia. BACKGROUND Ventricular distensibility is a major determinant of left ventricular end-diastolic pressure. The effects of graded myocardial ischemia on the regional distensibility of the ischemic area have not been studied. Moreover, there are few data on the effects of myocardial ischemia on the regional distensibility of the nonischemic myocardium. METHODS Nine anesthetized open chest mongrel dogs were fitted with instruments to measure left ventricular pressure and circumferential length (sonomicrometry) in the ischemic segment and in a nonischemic segment. The pressure-length relation was modified by stepwise infusion and withdrawal of 200 ml of each dogs own blood over 30 min in five consecutive stages of regional ischemia. Unstressed dimensions were obtained by repeated inferior vena cava occlusions. In both segments, regional distensibility was assessed at end-diastole by means of the constants of the pressure-length (chamber stiffness), the pressure-strain and the force-strain (myocardial stiffness) relations. RESULTS In the ischemic segment, partial and complete coronary occlusions were associated with a twofold increase in the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant, whereas in the nonischemic segment the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant increased by 50%. CONCLUSIONS Regional myocardial ischemia is associated with a decrease in distensibility of both the ischemic and the remote nonischemic myocardium.

Imaging opioid analgesia in the human brain and its potential relevance for understanding opioid use in chronic pain.

Opioids play an important role for the management of acute pain and in palliative care. The role of long-term opioid therapy in chronic non-malignant pain remains unclear and is the focus of much clinical research. There are concerns regarding analgesic tolerance, paradoxical pain and issues with dependence that can occur with chronic opioid use in the susceptible patient. In this review, we discuss how far human neuroimaging research has come in providing a mechanistic understanding of pain relief provided by opioids, and suggest avenues for further studies that are relevant to the management of chronic pain with opioids. This article is part of the Special Issue Section entitled ‘Neuroimaging in Neuropharmacology’.

Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development.

Background:Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. Methods:The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Results:Only gabapentin suppressed the secondary mechanical hyperalgesia–evoked neural response in a region of the brainstem’s descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Conclusions:Functional imaging with central sensitization can be used as a sensitive mechanism–based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.

Hemodynamic effects during induction, laryngoscopy, and intubation with eltanolone (5β-pregnanolone) or propofol. A study in ASA I and II patients

STUDY OBJECTIVE To evaluate the cardiovascular changes following induction of anesthesia, laryngoscopy, and intubation in patients receiving a bolus dose of either eltanolone or propofol. DESIGN Randomized, controlled, blind, prospective clinical study. SETTING General operating theaters of a university hospital. PATIENTS 40 ASA status I and II patients scheduled for elective surgery. INTERVENTIONS Patients were premedicated with oral temazepam 20 mg. Anesthesia was induced with either eltanolone 0.58 mg/kg or propofol 1.7 mg/kg, neuromuscular blockade was achieved with vecuronium 0.1 mg/kg, and anesthesia was maintained with enflurane 0.5% to 1.0% in nitrous oxide (67%). MEASUREMENTS AND MAIN RESULTS Blood pressure was measured using an automatic oscillometric technique, heart rate (HR) was derived from the ECG, oxygen saturation was measured by pulse oximetry, and cardiac output (Q) was measured by a thoracic bioimpedance technique. Induction of anesthesia with either drug, eltanolone or propofol, decreased arterial systolic (SAP) and diastolic (DAP) blood pressure, Q, and stroke volume (SV). HR increased. Systemic vascular resistance (SVR) was unaltered. After laryngoscopy and intubation, SAP and DAP increased secondary to an increase in SVR. HR also increased; SV decreased in patients receiving eltanolone. Side effects (e.g., apnea occurring for more than 30 seconds, involuntary movements, limb hypertonus) occurred at a similar incidence with both treatments, but pain following injection was greater with propofol (59% vs. 9%). CONCLUSIONS Patients receiving either eltanolone or propofol showed similar cardiovascular changes to induction of anesthesia, although there were greater increases in arterial pressure and HR in those patients receiving eltanolone.