Opioid Blockade Research Articles

Slow Release Naltrexone Implant vs Oral Naltrexone for Improving Treatment Outcomes in Opioid Addicted Participants with HIV: A Randomised Trial

Background: Untreated opioid addiction in persons with HIV is associated with poor outcome. Agonist maintenance is not always available and some do not want it. Slow release naltrexone may be a useful option. Methods: The study was a 48-week trial in which 200 opioid addicted patients starting antiretroviral treatment (ART) for HIV were stratified according to gender, viral load (VL) and CD4 count, and randomized to addiction treatment using a naltrexone implant and oral naltrexone placebo (NI; n=100), or oral naltrexone 50 mg/day and a placebo implant (ON; n=100). Research staff was blinded to group assignment. Primary outcome was plasma VL<400 copies at 24 and 48 weeks. All participants were included in the outcome analyses according to intention to treat principles. Findings: There was no difference between NI and ON in the number of participants with VL<400 copies at week 24 (38 [38%] vs 35 [35%] p=0*77) but more NI than ON participants had a VL<400 copies at week 48 (66 [66%] vs 50 [50%] RR: 1*32 [95% CI: 1*04-1*68] p=0*0451). Regardless of group assignment, those who continued naltrexone at 24 weeks more commonly had VL<400 copies than discontinuers (51 [70 %] vs 22 [30%] RR: 2*89 [95% CI: 1*91-4*38] p<0*0001) with similar findings at week 48 (VL <400 copies (64 [55%] vs 52 [44%] RR: 1*53 [95% CI: 1*21-1*95] p=0*0005). There were seven serious adverse events registered: three deaths in NI (one heart disease, one trauma, one AIDS), and four in ON (two overdoses, one pancreatic cancer, one AIDS). The overdose deaths occurred 9-10 months after the last naltrexone dose. Interpretation: An implant that is approved in the Russian Federation and provides opioid blockade for three months caused no serious adverse events and improved retention and outcome of persons with opioid addiction and HIV. Clinical Trial Number: The trial is registered at ClinicaTrials.gov, NCT02046252. Funding Statement: NIDA Grants: R01 DA026336; K05 DA17009; U10 DA013043; UG1 DA013034; Penn Center for AIDS Research P30 A1045008; Penn Mental Health AIDS Research Center P30 MH097488 Declaration of Interests: Fidelity Capital provided Prodetoxon®) at a reduced price and Prodetoxon placebo at no charge. Dr. Woody is a consultant to BICX102, a company that submitted a grant to NIDA requesting funds to develop and test a similarly-designed implant that could be submitted to the FDA for approval in the U.S. Dr. Krupitsky was a consultant to Alkermes in 2008-2011 and was a consultant for Prodetoxon LTD in 2017. Ethics Approval Statement: The protocol and consents were written in English, translated into Russian, reviewed by bilingual staff in Russia and the U.S, and approved by human subjects’ committees (IRBs) at First Pavlov State Medical University and the University of Pennsylvania. The sponsor and the two IRBs did annual reviews of study progress and reports of adverse events.

Early life adversity diminishes the cortisol response to opioid blockade in women: Studies from the Family Health Patterns project.

Early life adversity (ELA) contributes to behavioral impulsivity along with risk for substance use disorders, both accompanied by blunted stress-axis reactivity. However, the biological contributors to blunted stress reactivity are not known. We took advantage of the fact that women have significant opioid inhibition of cortisol output by using the opioid antagonist, naltrexone, to unmask opioid interactions due to ELA. We administered 50 mg of naltrexone or placebo to 72 healthy women (23 years of age) in a double-blind crossover study and observed deviations in cortisol secretion from placebo over the next 180 minutes. ELA was assessed by reported exposure to physical and sexual abuse or neglect and low socioeconomic status and scored as Low, Medium, or High (0, 1–2, and 3+). The ELA groups all had identical placebo-day cortisol secretion, indicating normal basal regulation of the hypothalamic-pituitary-adrenocortical axis. Cortisol rises to naltrexone were largest in the Low-ELA group and strongly blunted in the High-ELA group (F = 3.51, p = 0.035), indicating a lack of opioid function in women with high degrees of ELA. The Low-ELA women reported dysphoric responses to naltrexone (F = 4.05, p = .022) indicating a mild opioid withdrawal, an effect that was absent in the High-ELA group. Women exposed to ELA have blunted cortisol responses to naltrexone, indicating reduced opioid regulation of the stress axis. Central opioid changes may be one pathway linking ELA to blunted stress reactivity in adulthood.

Cue reactivity and opioid blockade in amphetamine dependence: A randomized, controlled fMRI study

BackgroundThe opioid antagonist, naltrexone, has been shown to reduce the risk of relapse in amphetamine dependence, but the mechanisms behind this effect are not well understood. We aimed to investigate if naltrexone attenuates cue reactivity and craving in amphetamine dependence. MethodsForty men with severe, intravenous amphetamine dependence were randomized to one dose of naltrexone (50 mg) or placebo. In a BOLD fMRI cue reactivity paradigm, they were exposed to drug-related and neutral films and gave subjective ratings of craving after each film. Twenty-nine patients left data of sufficient quality to be included in the final analysis. ResultsThe drug-related films elicited strong subjective craving and BOLD activations of the striatum, cingulate cortex, and occipito-temporal visual attention networks. Longer history of amphetamine use was associated with greater activations of the prefrontal cortex. Naltrexone as compared to placebo had no significant effects on brain activations or subjective ratings. ConclusionPatients with severe stimulant use disorder exhibit strong neural cue reactivity, the patterns of which are modulated by duration of drug use. In this sample, we found no evidence for any effects of naltrexone on cue reactivity.

Endocannabinoid-Enhanced "Liking" in Nucleus Accumbens Shell Hedonic Hotspot Requires Endogenous Opioid Signals.

Introduction: Stimulating either endogenous cannabinoids or opioids within a restricted dorsomedial “hedonic hotspot” in nucleus accumbens (NAc) shell enhances hedonic impact, or “liking” reactions to sweet tastes. In this study, we probed within this hotspot the relationship between endocannabinoid and opioid signals in hedonic enhancement.Materials and Methods: Specifically, we asked whether enhancement of sucrose “liking” by intra-NAc microinjections of the endocannabinoid anandamide requires concurrent endogenous opioid signaling.Results: Co-administration of the opioid antagonist naloxone in the same NAc microinjections with anandamide prevented the endocannabinoid from enhancing orofacial “liking” reactions to sucrose. Since intra-NAc hotspot naloxone injection alone failed to affect hedonics, reversal of anandamide-induced “liking” by opioid blockade reveals an interdependence of opioid and cannabinoid signaling in enhancing taste hedonic impact.Conclusions: These results elaborate our understanding of the mechanisms of hedonic processing of food rewards, and may also carry implications more generally for how opioid and cannabinoid drugs interact to generate natural pleasures, or drug-induced euphoria.

P.6.d.003 - Cue reactivity and opioid blockade in amphetamine dependence: a randomised, controlled fMRI study

P.6.d.003 - Cue reactivity and opioid blockade in amphetamine dependence: a randomised, controlled fMRI study

Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder

Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation. To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD. This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit). A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13). The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes. A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg). CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits. Clinicaltrials.gov Identifier: NCT02611752.

P.6.d.014 - Endogenous opioid blockade modulates neural networks implicated in attentional and behavioural control in individuals recovering from alcohol and drug dependence

P.6.d.014 - Endogenous opioid blockade modulates neural networks implicated in attentional and behavioural control in individuals recovering from alcohol and drug dependence

The Effects of Pharmacological Opioid Blockade on Neural Measures of Drug Cue-Reactivity in Humans.

Interactions between dopaminergic and opioidergic systems have been implicated in the reinforcing properties of drugs of abuse. The present study investigated the effects of opioid blockade, via naltrexone, on functional magnetic resonance imaging (fMRI) measures during methamphetamine cue-reactivity to elucidate the role of endogenous opioids in the neural systems underlying drug craving. To investigate this question, non-treatment seeking individuals with methamphetamine use disorder (N=23; 74% male, mean age=34.70 (SD=8.95)) were recruited for a randomized, placebo controlled, within-subject design and underwent a visual methamphetamine cue-reactivity task during two blood-oxygen-level dependent (BOLD) fMRI sessions following 3 days of naltrexone (50 mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation and functional connectivity during cue processing. The results showed that naltrexone administration reduced cue-reactivity in sensorimotor regions and related to altered functional connectivity of dorsal striatum, ventral tegmental area, and precuneus with frontal, visual, sensory, and motor-related regions. Naltrexone also weakened the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthened the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions. In conclusion, this study provides the first evidence that opioidergic blockade alters neural responses to drug cues in humans with methamphetamine addiction and suggests that naltrexone may be reducing drug cue salience by decreasing the involvement of sensorimotor regions and by engaging greater frontal regulation over salience attribution.

Touch Perception Altered by Chronic Pain and by Opioid Blockade.

Touch plays a significant role in human social behavior and social communication, and its rewarding nature has been suggested to involve opioids. Opioid blockade in monkeys leads to increased solicitation and receipt of grooming, suggesting heightened enjoyment of touch. We sought to study the role of endogenous opioids in perception of affective touch in healthy adults and in patients with fibromyalgia, a chronic pain condition shown to involve reduced opioid receptor availability. The pleasantness of touch has been linked to the activation of C-tactile fibers, which respond maximally to slow gentle touch and correlate with ratings of pleasantness. We administered naloxone to patients and healthy controls to directly observe the consequences of µ-opioid blockade on the perceived pleasantness and intensity of touch. We found that at baseline chronic pain patients showed a blunted distinction between slow and fast brushing for both intensity and pleasantness, suggesting reduced C-tactile touch processing. In addition, we found a differential effect of opioid blockade on touch perception in healthy subjects and pain patients. In healthy individuals, opioid blockade showed a trend toward increased ratings of touch pleasantness, while in chronic pain patients it significantly decreased ratings of touch intensity. Further, in healthy individuals, naloxone-induced increase in touch pleasantness was associated with naloxone-induced decreased preference for slow touch, suggesting a possible effect of opioid levels on processing of C-tactile fiber input. These findings suggest a role for endogenous opioids in touch processing, and provide further evidence for altered opioid functioning in chronic pain patients.

GABA and enkephalin tonically alter sympathetic outflows in the rat spinal cord.

GABA and enkephalin provide significant innervation of sympathetic preganglionic neurons. Despite some investigation as to the identity of premotor sources of these innervations no comprehensive analyses have been conducted. Similarly, although data describing the cardiovascular effects of blockade of GABAA receptors in the spinal cord is available, the effects at other sympathetic outflows are unknown. In contrast the sympathetic effects of opioid blockade in the spinal cord are unclear. The aims of this study were to identify potential sympathetic premotor sources of GABAergic and enkephalinergic input to the spinal cord and to describe the sympathetic and cardiovascular effects of spinal GABAA receptor and delta/mu opioid receptor blockade in urethane anaesthetised rats. Glutamic acid decarboxylase (GAD67) and preproenkephalin (PPE) mRNA were found in all regions containing sympathetic premotor neurons, with the medullary raphe and RVMM providing the major GABAergic projections, while the PVN, RVMM and medullary raphe provided the major enkephalinergic projections. Intrathecal injection of bicuculline, a GABAA antagonist, elicited large and prolonged increases in all outflows measured, confirming previous work describing a tonic GABAergic influence on vasomotor tone, and revealing a tonic GABAergic inhibition of interscapular brown adipose tissue temperature. Intrathecal naloxone elicited transient small inhibitory effects only on MAP and HR. Thus GABA acting in the spinal cord plays an important role in the tonic suppression of sympathetic outflows while enkephalin appears to play only a minor role.

Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent μ-Receptor Antagonist.

A novel clinical study design was used to evaluate the blockade of a selective short-acting μ-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with μ-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t½ = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective μ-opioid effects.

Skin β-Endorphin Mediates Addiction to UV Light

UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, β-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in β-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of β-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans.

Endogenous Opioid Inhibition of Chronic Low-Back Pain Influences Degree of Back Pain Relief After Morphine Administration

Factors underlying differential responsiveness to opioid analgesic medications used in chronic pain management are poorly understood. We tested whether individual differences in endogenous opioid inhibition of chronic low-back pain were associated with the magnitude of acute reductions in back pain ratings after morphine administration. In randomized counterbalanced order over three sessions, 50 chronic low-back pain patients received intravenous naloxone (8 mg), morphine (0.08 mg/kg), or placebo. Back pain intensity was rated predrug and again after peak drug activity was achieved using the McGill Pain Questionnaire-Short Form (Sensory and Affective subscales, VAS Intensity measure). Opioid blockade effect measures to index degree of endogenous opioid inhibition of back pain intensity were derived as the difference between predrug to postdrug changes in pain intensity across placebo and naloxone conditions, with similar morphine responsiveness measures derived across placebo and morphine conditions. Morphine significantly reduced back pain compared with placebo (McGill Pain Questionnaire-Short Form Sensory, VAS; P < 0.01). There were no overall effects of opioid blockade on back pain intensity. However, individual differences in opioid blockade effects were significantly associated with the degree of acute morphine-related reductions in back pain on all measures, even after controlling for effects of age, sex, and chronic pain duration (P < 0.03). Individuals exhibiting greater endogenous opioid inhibition of chronic back pain intensity reported less acute relief of back pain with morphine. Morphine appears to provide better acute relief of chronic back pain in individuals with lower natural opioidergic inhibition of chronic pain intensity. Possible implications for personalized medicine are discussed.

A new biomarker of hedonic eating? A preliminary investigation of cortisol and nausea responses to acute opioid blockade

Overweight and obese individuals differ in their degree of hedonic eating. This may reflect adaptations in reward-related neural circuits, regulated in part by opioidergic activity. We examined an indirect, functional measure of central opioidergic activity by assessing cortisol and nausea responses to acute opioid blockade using the opioid antagonist naltrexone in overweight/obese women (mean BMI=31.1±4.8) prior to the start of a mindfulness-based intervention to reduce stress eating. In addition, we assessed indices of hedonic-related eating, including eating behaviors (binge eating, emotional eating, external eating, restraint) and intake of sweets/desserts and carbohydrates (Block Food Frequency); interoceptive awareness (which is associated with dysregulated eating behavior); and level of adiposity at baseline. Naltrexone-induced increases in cortisol were associated with greater emotional and restrained eating and lower interoceptive awareness. Naltrexone-induced nausea was associated with binge eating and higher adiposity. Furthermore, in a small exploratory analysis, naltrexone-induced nausea predicted treatment response to the mindfulness intervention, as participants with more severe nausea at baseline maintained weight whereas those with little or no nausea responses tended to gain weight. These preliminary data suggest that naltrexone-induced cortisol release and nausea may help identify individuals who have greater underlying food reward dependence, which leads to an excessive drive to eat. Future research is needed to confirm this finding and to test if these markers of opioidergic tone might help predict success in certain types of weight management programs.

The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: A randomized double-blind placebo-controlled pilot study

Olanzapine (OLZ), a commonly prescribed second generation antipsychotic drug, is associated with obesity and metabolic syndrome and may contribute to increased cardiovascular morbidity and mortality. Opioidergic neurotransmission may be implicated in the development of these metabolic disturbances. The objective of this study was to assess the effects of opioid blockade on OLZ-treated patients' metabolic status. Patients with schizophrenia or schizoaffective disorder (n=30) on a stable dose of OLZ were randomized in a double-blind fashion to receive an opioid receptor antagonist, naltrexone (NTX), (n=14) or placebo (n=16). The primary outcome measure was the change in body mass index (BMI) at 12 weeks. Secondary measures included body fat and fat-free mass, along with homeostasis model assessment-estimated insulin resistance (HOMA-IR), plasma lipids and liver function tests (LFTs). There was no significant change in BMI between the treatment arms. However, in comparison to the OLZ + placebo combination, the OLZ + NTX group displayed a significant decrease in the fat and increase in fat-free mass along with a trend towards improvement in HOMA-IR values. There were no significant differences in plasma lipids and LFTs. These findings suggest that addition of NTX to OLZ may attenuate OLZ-induced body fat mass gain. A larger study of longer duration will be needed to confirm these results.

Opioid receptor blockade and warmth-liking: effects on interpersonal trust and frontal asymmetry

The emotion 'warmth-liking' (WL) associated with feelings of affection and acceptance is regularly activated in social contexts. WL has been suggested to be more closely related to the consummatory phase of post-goal attainment positive affect than to pre-goal attainment positive affect/approach motivation and to be partly mediated by brain opioids. To validate these assumptions we employed film/imagery to induce either a neutral emotional state or WL in female participants after intake of either placebo or the opioid antagonist naltrexone. Dependent variables were emotion self-report, interpersonal trust (TRUST, i.e. a behavioral indicator of WL) and frontal asymmetry (i.e. an electroencephalogram (EEG) indicator of approach motivation/behavioral activation). We found that participants reported more WL in the placebo/WL group than in the placebo/neutral group and both naltrexone groups. In addition, TRUST increased in the WL group after placebo, but not after naltrexone, and this pattern was reversed in the neutral control groups. Consequently, opioid blockade suppressed or even reversed the effects of the WL induction on the levels of self-report and behavior, respectively. In addition, we observed reduced relative left-frontal asymmetry in the WL (vs neutral) group, consistent with reduced approach motivation. Overall, these results suggest opioidergic influences on WL and TRUST and reduced approach motivation/behavioral activation for the positive emotion WL.

Anger regulation style, anger arousal and acute pain sensitivity: evidence for an endogenous opioid “triggering” model

Findings suggest that greater tendency to express anger is associated with greater sensitivity to acute pain via endogenous opioid system dysfunction, but past studies have not addressed the role of anger arousal. We used a 2×2 factorial design with Drug Condition (placebo or opioid blockade with naltrexone) crossed with Task Order (anger-induction/pain-induction or pain-induction/anger-induction), and with continuous Anger-out Subscale scores. Drug×Task Order×Anger-out Subscale interactions were tested for pain intensity during a 4-min ischemic pain task performed by 146 healthy people. A significant Drug×Task Order×Anger-out Subscale interaction was dissected to reveal different patterns of pain intensity changes during the pain task for high anger-out participants who underwent pain-induction prior to anger-induction compared to those high in anger-out in the opposite order. Namely, when angered prior to pain, high anger-out participants appeared to exhibit low pain intensity under placebo that was not shown by high anger-out participants who received naltrexone. Results hint that people with a pronounced tendency to express anger may suffer from inadequate opioid function under simple pain-induction, but may experience analgesic benefit to some extent from the opioid triggering properties of strong anger arousal.

Naltrexone Accelerates Full‐Thickness Cutaneous Wound Healing by Enhancing Remodeling

Patients with Type 1 diabetes (T1D) risk complications from impaired wound healing, and the pathophysiology of wound repair is poorly understood. Delayed repair of full‐thickness cutaneous wounds in T1D rats is reversed by blockade of the opioid growth factor receptor (OGFr) with topically applied naltrexone (NTX), an opioid antagonist. NTX accelerates wound closure and angiogenesis of cutaneous wounds in both T1D and normal rats. To evaluate wound remodeling, streptozotocin‐induced T1D rats, and normal rats, with 6 mm cutaneous wounds, were topically treated with NTX or sterile saline in moisturizing cream (3x/day) for 20 days. Tissue specimens were evaluated for tensile strength, matrix metalloproteinase‐9 (MMP‐9) expression and collagen maturation. Collagen maturation, as measured by Sirius red staining, revealed that T1D NTX‐treated wounds showed a 45‐fold increase in maturation compared to T1D controls after 20 days of treatment. On day 20, T1D controls had significantly less MMP‐9 expression within the wound compared to T1D NTX‐treated and normal rats. By day 60 post‐wounding, tensile strength values of wounds in T1D rats treated with NTX were comparable to those in normal rats, whereas vehicle treated T1D wounds displayed significantly lower tensile strengths. In summary, blockade of endogenous opioids by NTX provided a non‐toxic biological treatment that accelerated wound remodeling in T1D rats.Grant Funding Source: American Diabetes Association

Naloxone-Reversible Modulation of Pain Circuitry by Left Prefrontal rTMS

A 20-minute session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) of Brodmann Area (BA) nine of the left dorsolateral prefrontal cortex (DLPFC) can produce analgesic effects on postoperative and laboratory-induced pain. This analgesia is blocked by pretreatment with naloxone, a μ-opioid antagonist. The purpose of this sham-controlled, double-blind, crossover study was to identify the neural circuitry that underlies the analgesic effects of left DLPFC rTMS, and to examine how the function of this circuit, including midbrain and medulla, changes during opioid blockade. Fourteen healthy volunteers were randomized to receive intravenous saline or naloxone immediately before sham and real left DLPFC rTMS on the same experimental visit. One week later, each participant received the novel pretreatment but the same stimulation paradigm. Using short sessions of heat on capsaicin-sensitized skin, hot allodynia was assessed during 3 Tesla functional magnetic resonance imaging (fMRI) scanning at baseline, post-sham rTMS, and post-real rTMS. Data were analyzed using whole-brain voxel-based analysis, as well as time series extractions from anatomically-defined regions of interest representing midbrain and medulla. Consistent with previous findings, real rTMS significantly reduced hot allodynia pain ratings. This analgesia was associated with elevated blood oxygenation-level dependent (BOLD) signal in BAs 9 and 10, and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and medulla during pain. Naloxone pretreatment largely abolished rTMS-induced analgesia, as well as rTMS-induced attenuation of BOLD signal response to painful stimuli throughout pain processing regions, including midbrain and medulla. These preliminary results suggest that left DLPFC rTMS drives top-down opioidergic analgesia.

SUNCT and SUNA: Recognition and Treatment

The problem of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) management remains unsolved. Despite a myriad of therapeutic trials, no convincingly effective remedy for SUNCT and SUNA is available at present. Based on open-label communications, some patients seemed to benefit from some pharmacologic, interventional, or invasive procedures. Possible effective preventive drugs are carbamazepine, lamotrigine, gabapentin, and topiramate. At present, the drug of choice for SUNCT seems to be lamotrigine whereas SUNA may better respond to gabapentin. There is no available abortive treatment for the individual attacks. During the worst periods, intravenous lidocaine may decrease the flow of SUNCT/SUNA attacks. In SUNCT, bilateral blockade of the greater occipital nerve, and superior cervical ganglion opioid blockade have been reported as temporary/partially effective in one patient each. Botulinum toxin injected around the symptomatic orbit provided sustained relief to one patient. Owing to the scarcity of reports the results of these interventions should be taken as preliminary. Invasive therapy with interventions directed to the first division of the trigeminal nerve or Gasserian ganglion, with local anesthetics or alcohol, radiofrequency thermocoagulation, microvascular decompression, and gamma-knife neurosurgery, have been tried in the treatment of refractory SUNCT. Some patients seemed to benefit from such interventions, but one should still have a critical attitude to these claims since no convincing results have been obtained as yet. The few SUNCT patients who underwent deep brain hypothalamic stimulation obtained a substantial and persistent relief.