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Chronic low back pain (cLBP) is the most prevalent chronic pain condition. There are no treatments that haven been found to directly assuage evoked cLBP. To this extent, mindfulness-meditation is a promising pain therapy. Yet, it is unclear if meditation can be utilized to directly attenuate evoked chronic pain through endogenous opioids. A double-blind, randomized, and placebo-controlled clinical trial with a drug crossover design examined if mindfulness-meditation, as compared to sham mindfulness-meditation, attenuated straight leg-raise test evoked chronic pain during intravenous (0.15 mg/kg bolus + 0.15 mg/kg/hour maintenance) naloxone (opioid antagonist) and placebo-saline infusion. Fifty-nine individuals with cLBP (mean age = 46 years; 30 females) completed all study procedures. After the pre-intervention pain testing session, patients were randomized to a four-session (20-min/session) mindfulness (n = 30) or sham mindfulness-meditation (n = 29) intervention. After the interventions, mindfulness and sham mindfulness-meditation were associated with significant reductions in back pain during saline and naloxone infusion when compared to rest (non-meditation) in response to the cLBP-evoking straight leg-raise test. These results indicate that meditation directly reduces evoked chronic pain through non-opioidergic processes. Importantly, after the interventions, the mindfulness group reported significantly lower straight leg-raise induced pain than the sham mindfulness-meditation group during rest (non-meditation) and meditation. Mindfulness and sham mindfulness-meditation training was also associated with significantly lower Brief Pain Inventory severity and interference scores. The pain-relieving effects of mindfulness meditation were more pronounced than a robust sham-mindfulness meditation intervention, suggesting that non-reactive appraisal processes may be uniquely associated with improvements in chronic low-back pain.Trial Registration: ClinicalTrials.gov identifier: NCT04034004.

Severe chronic postsurgical pain has a prevalence of 4–10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm 2 ). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile (‘high-sensitizers’ [n = 20]) and the lower quartile (‘low-sensitizers’ [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between ‘high-sensitizers’ and ‘low-sensitizers’ (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for ‘high-sensitizers’ (P < 0.001), but not ‘low-sensitizers’ (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

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.

Background Recent studies suggest that participant expectations influence pain ratings during conditioned pain modulation testing. The present study extends this work by examining expectancy effects among individuals with and without chronic back pain after administration of placebo, naloxone, or morphine. Purpose This study aims to identify the influence of individual differences in expectancy on changes in heat pain ratings obtained before, during, and after a forearm ischemic pain stimulus. Methods Participants with chronic low back pain ( n  = 88) and healthy controls ( n  = 100) rated heat pain experience (i.e., “test stimulus”) before, during, and after exposure to ischemic pain (i.e., “conditioning stimulus”). Prior to testing, participants indicated whether they anticipated that their heat pain would increase, decrease, or remain unchanged during ischemic pain. Results Analysis of the effects of expectancy (pain increase, decrease, or no change), drug (placebo, naloxone, or morphine), and group (back pain, healthy) on changes in heat pain revealed a significant main effect of expectancy ( p  = 0.001), but no other significant main effects or interactions. Follow-up analyses revealed that individuals who expected lower pain during ischemia reported significantly larger decreases in heat pain as compared with those who expected either no change ( p  = 0.004) or increased pain ( p  = 0.001). Conclusions The present findings confirm that expectancy is an important contributor to conditioned pain modulation effects, and therefore significant caution is needed when interpreting findings that do not account for this individual difference. Opioid mechanisms do not appear to be involved in these expectancy effects.

Rationale Tramadol is an atypical, mixed-mechanism analgesic involving both opioid and catecholamine processes that appears to have low abuse potential and may be useful as a treatment for opioid dependence. Objectives The current study assessed the level of physical dependence and opioid blockade efficacy produced by daily maintenance on oral tramadol. Methods Nine residential opioid-dependent adults were maintained on two doses of daily oral tramadol (200 and 800 mg) for approximately 4-week intervals in a randomized, double-blind, crossover design. The acute effects of intramuscular placebo, naloxone (0.25, 0.5, and 1.0 mg), and hydromorphone (1.5, 3.0, and 6.0 mg) were tested under double-blind, randomized conditions. Outcomes included observer- and subject-rated measures and physiologic indices. Results Challenge doses of naloxone resulted in significantly higher mean peak withdrawal scores compared to placebo. Withdrawal intensity from naloxone was generally greater during 800 versus 200 mg/day tramadol maintenance. Mean peak ratings of agonist effects were elevated at higher hydromorphone challenge doses, but did not differ significantly between tramadol doses. Physiologic measures were generally affected by challenge conditions in a dose-dependent manner, with few differences between tramadol maintenance dose conditions. Conclusions Chronic tramadol administration produces dose-related opioid physical dependence, without producing dose-related attenuation of agonist challenge effects. Tramadol may be a useful treatment for patients with low levels of opioid dependence or as a treatment for withdrawal during opioid detoxification, but does not appear to be effective as a maintenance medication due to a lack of opioid cross-tolerance.

Background Controlled‐release oxycodone/naloxone (OXN‐CR) maintains the effect of opioid‐induced analgesia through oxycodone while reducing the occurrence rate of opioid‐induced constipation through naloxone. The present study was designed to assess the non‐inferiority of OXN‐CR to controlled‐release oxycodone (OX‐CR) for the control of cancer‐related pain in Korean patients. Methods In this randomized, open‐labeled, parallel‐group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer‐related pain [numeric rating scale (NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention‐to‐treat (ITT) population were randomized (1:1) to OXN‐CR or OX‐CR groups. OXN‐CR was administered starting at 20 mg/10 mg per day and up‐titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX‐CR was administered starting at 20 mg/day and up‐titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non‐inferiority margin of −1.5. Secondary endpoints included analgesic rescue medication intake, patient‐reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments. Results Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN‐CR group (n = 58) and the OX‐CR group (n = 59) (−1.586 vs. −1.559, P = 0.948). The lower limit of the one‐sided 95% confidence interval (−0.776 to 0.830) for the difference exceeded the non‐inferiority margin (P < 0.001). The OXN‐CR and OX‐CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments. Conclusions OXN‐CR was non‐inferior to OX‐CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer‐related pain are needed to further investigate the effectiveness of OXN‐CR for long‐term pain control and constipation alleviation. Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011

Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury. Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds. Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects. Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

Rationale Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence. Objectives The present study investigated the effects of buprenorphine alone and in combination with naloxone administered intramuscularly and sublingually to non-dependent opioid abusers. Methods In a within-subject crossover design, non-dependent opioid-experienced volunteers ( N  = 8) were administered acute doses of buprenorphine (4, 8, and 16 mg) and buprenorphine/naloxone (4/1, 8/2, and 16/4 mg) via both intramuscular and sublingual routes, intramuscular hydromorphone (2 and 4 mg as an opioid agonist control), and placebo, for a total of 15 drug conditions. Laboratory sessions were conducted twice per week using a double-blind, double-dummy design. Results Buprenorphine and buprenorphine/naloxone engendered effects similar to hydromorphone. Intramuscular administration produced a greater magnitude of effects compared to the sublingual route at the intermediate dose of buprenorphine and at both the low and high doses of the buprenorphine/naloxone combination. The addition of naloxone did not significantly alter the effects of buprenorphine. Conclusions These results suggest that buprenorphine and buprenorphine/naloxone have similar abuse potential in non-dependent opioid abusers, and that the addition of naloxone at these doses and in this dose ratio confers no evident advantage for decreasing the abuse potential of intramuscular or sublingual buprenorphine in this population.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4–2 mg. Naloxone is rapidly eliminated [half-life ( t 1/2 ) 60–120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration ( T max ) 15–30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4–0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Objective: Preclinical and clinical findings suggest a substantial association of the endogenous opioid system in nicotine dependence. The present study investigates the possible dose-dependent influence of naloxone, an unspecific opioid-receptor-antagonist, combined with cue exposure on the physiological state, locomotor activity, craving and the hypothalamic-pituitary-adrenal axis in nicotine-dependent humans. Methods: Twenty nicotine-dependent, outpatient participants were deprived of nicotine for over 4 h, before receiving challenges with naloxone (1.6 mg or 3.2 mg q70 kg IV) or the placebo. Additionally, following drug administration, either smoking-related cues or neutral images were presented. Nicotine withdrawal was monitored by evaluating the following objective signs – skin conductance, heart rate, temperature, respiration, locomotor activity, cortisol, prolactin and ACTH levels as well as craving. Results: With respect to subjective effects, participants administered a higher dosage of naloxone and those who were shown smoking-related cues were significantly less pleased (p = 0.019), felt more depressed (p = 0.033) and thought smoking would make them feel better (p = 0.028) than participants given naloxone and shown neutral cues. Participants given no naloxone but with smoking-related cues felt a higher urge to smoke than participants given naloxone and shown neutral cues (p = 0.042). Naloxone – in both dosages – also decreased the desire and intention to smoke in comparison to placebo. Compared to the placebo group, significantly higher cortisol, prolactin and ACTH values were observed after administration of lower and higher dosage of naloxone followed by smoking-related cues. Conclusion: Naloxone influenced nicotine withdrawal and strengthened significantly by cue exposure, both on objective measurement and on craving scales. These findings suggest an involvement of the endogenous opioid system in the development and maintenance of nicotine dependence.